Azaindole derivatives as kinase inhibitors

ABSTRACT

This invention relates to compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use.

BACKGROUND OF THE INVENTION

The protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processesand maintain control over cellular function. A partial, non limiting,list of such kinases includes ALK, abl, Akt, bcr-abl, Blk, Brk, c-kit,c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9,CDK10, bRaf, cRaf1, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Pak, fes,FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, flt-3, Fps, Frk, Fyn,Hck, IGF-1R, INS-R, Jak1, Jak2, Jak3, KDR, Lck, Lyn, FAK, MEK, p38,PDGFR, PIK, PKC, PYK2, ros, tie, tie2, Pim-1, P13k, TRK and Zap70.Abnormal protein kinase activity has been related to several disorders,ranging from non-life threatening diseases such as psoriasis toextremely serious diseases such as cancers.

In view of this large number of protein kinases and the multitude ofprotein kinase-related diseases, there is an ever-existing need toprovide new classes of compounds with increased selectivity that areuseful as protein kinase inhibitors and therefore useful in thetreatment of protein tyrosine-kinase related diseases.

This invention concerns a new family of Azaindole compounds and theiruse in treating cancers and other diseases.

DESCRIPTION OF THE INVENTION 1. General Description of Compounds of theInvention

The compounds of this invention have a broad range of useful biologicaland pharmacological activities, permitting their use in pharmaceuticalcompositions and methods for treating cancer (including lymphoma, solidtumors and leukemia among other cancers), including, also among others,advanced cases and cases which are resistant or refractory to one ormore other treatments.

Included are compounds of Formula I, and a tautomer and apharmaceutically acceptable salt and a solvate thereof:

wherein

Ring A is a 6-membered heteroaryl ring, comprising carbon atoms and 1 to3 nitrogen atoms; Ring A is substituted with Ring C at position 1 or atposition 2, and Ring A is optionally substituted with 1 or 2 R^(a)groups;

Ring B is a 5-membered heteroaryl ring, comprising carbon atoms and 1 to3 nitrogen atoms;

L¹ is C(O), CR⁴R⁵ or a bond;

X is O or NR⁴;

Ring C is an aryl, a 3- to 8-membered carbocyclyl or a 5-, 6- or7-membered heterocyclic or heteroaryl ring comprising carbon atoms and1-4 heteroatoms independently selected from O, N, P(O) and S(O)_(r);Ring C is optionally substituted on carbon or on the heteroatom(s) with1-5 R^(c) groups; and Ring C has a multiple point of attachment and canbe attached to either the depicted position 1 of Ring A or the depictedposition 2 of Ring A;

Ring D is an aryl or a 5- or 6-membered heteroaryl ring comprisingcarbon atoms and 1 to 4 heteroatoms independently selected from O, N andS, and Ring D is optionally substituted with 1 to 5 R^(d) groups;

R^(a) and R^(d) are independently selected from the group consisting ofhalo, —CN, —NO₂, —R¹, —OR², —O—NR¹R², —NR¹R², —NR¹—NR¹R², —NR¹—OR²,—C(O)YR², —OC(O)YR², —NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR²,—C(═S)YR², —YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR²,—YP(═O)(YR³)(YR³), —Si(R³)₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and—NR¹SO₂NR¹R²;

R^(c) is R^(a) or ═O or ═S;

or alternatively two adjacent R^(a) moieties, two adjacent R^(c)moieties or two adjacent R^(d) moieties can form with the atoms to whichthey are attached a 5-, 6- or 7-membered saturated, partially saturatedor unsaturated ring, optionally substituted; and which contains 0-4heteroatoms selected from N, O, P(O) and S(O)_(r);

r is 0, 1 or 2;

n is 0, 1 or 2;

p is 0, 1, 2, 3, 4 or 5;

s is 0, 1, 2, 3, 4 or 5;

each occurrence of Y is independently a bond, —O—, —S— or —NR¹—;

each occurrence of R¹ and R² is independently selected from H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heterocyclic and heteroaryl;

each occurrence of R³ is independently selected from alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic andheteroaryl;

R⁴ and R⁵ are independently selected from H or a C₁₋₆alkyl;

alternatively, each NR¹R² moiety may be a 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated ring, which can beoptionally substituted and which contains 0-3 additional heteroatomsselected from N, O, P(O) and S(O)_(r); and

each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl and heterocyclic moiety is optionallysubstituted.

The foregoing definitions are further elaborated upon and exemplifiedbelow and apply to all subsequent occurrences except to the extentotherwise specified.

2. Featured Classes of Compounds and their Use, Generally

One class of compounds which is of special interest for use in thisinvention are compounds of Formula I in which X is O. This class isillustrated by compounds of Formula II:

Another class of compounds of special interest are compounds of FormulaI which X is NR⁴. This class is illustrated by compounds of Formula III:

In one embodiment are compounds of Formulae I, II or III in which Ring Ahas the following formulae:

In one embodiment Ring C is attached to position 2 of Ring A.

In another embodiment, Ring C is attached to position 1 of Ring A.

In another embodiment are compounds of Formulae I, II, III or otherpreviously described classes in which Ring B has the following formulae:

In one particular embodiment of interest, Ring B is a pyrolle.

In another embodiment of interest, Ring B is a pyrazole or an imidazole.

One class of compounds which is of special interest for use in thisinvention are compounds of Formulae I, II or III in which Ring A ispyridine. This class of compound is illustrated by compounds of FormulaIV:

in which variable Rings B, C and D, X, L¹, R^(a), R^(c) and R^(d), n, sand p are as defined above in part 1.

Of further interest are compounds of Formulae IV in which Ring C isattached to position 2 of Ring A. This class of compounds is illustratedby compounds of Formula IVA:

Non limiting examples of this embodiment include compounds of formulaIVA of the following type:

Of other interest are compounds of Formulae IV in which Ring C isattached to position 1 of Ring A. This class is illustrated by compoundsof Formula IVB:

Non limiting examples of this embodiment include compounds of formulaIVB of the following type:

In one particular embodiment are compounds of Formulae IV, IVA and IVBin which X is O. In another embodiment of interest are compounds ofFormulae IV, IVA and IVB in which X is NR⁴.

In another embodiment of this invention, Ring A is a pyrazine. Thisclass is illustrated by compounds of Formula V:

Of further interest are compounds of Formula V in which Ring C isattached to position 2 of Ring A. This class of compounds is illustratedby compounds of Formula VA:

Of other interest are compounds of Formula V in which Ring C is attachedto position 1 of Ring A. This class is illustrated by compounds ofFormula VB:

In one particular embodiment are compounds of Formulae V, VA and VB inwhich X is O.

In another embodiment of interest are compounds of Formulae V, VA and VBin which X is NR⁴.

Non limiting examples of this embodiment include compounds of formulaeV, VA and VB of the following type:

For the previously described classes and subclasses of compounds, as inall compounds of the invention, Rings B, C and D, X, L¹, R^(a), R^(c)and R^(d), n, s and p are defined as in part 1.

In one embodiment are compounds of Formulae I, II, III, IV, IVA, IVB, V,VA, VB or any other classes and subclasses of this invention in whichRing C is an aryl optionally substituted with 1 to 5 R^(c) groups.

R^(c) is as defined previously in part 1. Of additional interest is aclass of compounds as described above in which R^(c) is selected fromthe group consisting of —R¹, —S(O)₂NR¹R², —S(O)₂R¹, —C(O)NR¹R², halo,—OR¹, —NR¹R², —NR¹C(O)R², —C(O)R², —P(O)(R³)₂. In another subclass ofinterest, are compounds of the above embodiment in which R^(c) is Cl, F,CF₃, —S(O)₂alkyl, —S(O)₂NHalkyl, —S(O)₂NH₂, —O-alkyl, optionallysubstituted alkyl, heterocyclyl, heteroaryl, aryl or —P(O)(alkyl)₂. Nonlimiting examples of substituted alkyl are —(CH₂)_(z)C(═O)NR¹R²,—(CH₂)_(z)NHC(═O)R², —(CH₂)_(z)NR¹R², —(CH₂)_(z)C(═O)OR¹,—(CH₂)_(z)heterocyclyl, —(CH₂)_(z)aryl, —(CH₂)_(z)heteroaryl,—(CH₂)_(z)S(═O)₂NR¹R² or —(CH₂)_(z)S(═O)₂R¹, in which z is 1, 2, 3 or 4and alkyl include straight (i.e. unbranched or acyclic), branched andcyclic alkyl groups and alkyl, aryl, heteroaryl, heterocyclyl groups areoptionally substituted.

In one particular aspect of the above embodiment, Ring C is a phenylsubstituted with 1-5 R^(c). Illustrative examples of Phenyl moietiessubstituted with R^(c) are:

In another embodiment are compounds of any of the above Formulae or anyother classes and subclasses of this invention in which Ring C is a 5-,6- or 7-membered heterocyclyl ring comprising carbon atoms and 1-4heteroatoms independently selected from O, N, P(O) and S(O)_(r), andRing C is substituted on carbon or on the heteroatom(s) with 1-5 R^(c)groups. It is understood that the total number of substituents R^(c)does not exceed the normal available valencies.

Non-limiting examples of this class are compounds of any of formulae Ito VB or of other previously described classes and subclasses in whichRing C is of the following types:

Non-limiting illustrative examples are compounds of the followingformulae:

In another embodiment, Ring C is a 5-, or 6-membered heteroaryl ringcomprising carbon atoms and 1-4 heteroatoms independently selected fromO, N and S(O)_(r).

In one embodiment are compounds of any of the above Formulae in whichRing C is a 5-membered ring heteroaryl comprising carbon atoms and 1-4Nitrogen atoms. Non-limiting examples of this class are compounds of theprevious classes and subclasses in which Ring C is of the followingtypes:

in which R^(c) and s are as previously defined. It is understood thatthe total number of substituents R^(c) does not exceed the normalavailable valencies.

In a particular aspect of this embodiment, Ring C has the followingformulae:

R^(c) is as defined previously in part 1. Of additional interest is aclass of compounds as described above in which R^(c) is selected fromthe group consisting of —R¹ and —C(O)YR². In another subclass ofinterest, are compounds of the above embodiment in which R^(c) is H,—C(O)R², —C(O)NR¹R², an aryl, heteroaryl, optionally substituted alkylor heterocyclyl. Non limiting examples of substituted alkyl are—(CH₂)_(z)C(═O)NR¹R², —(CH₂)_(z)NHC(═O)R², —(CH₂)_(z)NR¹R²,—(CH₂)_(z)C(═O)OR¹, —(CH₂)_(z)heterocyclyl, —(CH₂)_(z)aryl,—(CH₂)_(z)heteroaryl in which z is 1, 2, 3 or 4 and alkyl includestraight (i.e. unbranched or acyclic), branched and cyclic alkyl groupsand alkyl, aryl, heteroaryl, heterocyclyl groups are optionallysubstituted.

Illustrative examples of such compounds include those in whichsubstituent R^(c) is without limitation:

Other illustrative examples of this class include compounds in whichRing C is of the following types:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

In other embodiments, Ring C is a 5-membered ring heteroaryl comprisingcarbon atoms and 1-4 Nitrogen atoms and the heteroaryl ring is linked tothe core moiety via a nitrogen atom. Non-limiting examples includecompounds of the previous classes and subclasses in which the N-linkedRing C has the following formulae:

in which R^(c) and s are as previously defined. It is understood thatthe total number of substituents R^(c) does not exceed the normalavailable valencies. Thus, for example, when Ring C is an N-linkedpyrolle ring, it can be optionally substituted with 1 to 4 substituents(i.e. p is 0, 1, 2, 3 or 4), whereas when Ring C is an N-linked pyrazoleor an N-linked imidazole, it can only be optionally substituted with amaximum of 3 substituents (i.e. p is 0, 1, 2 or 3).

R^(c) is as defined previously in part 1. Of additional interest is aclass of compounds as described above in which R^(c) is selected fromthe group consisting of —R¹, halo, —OR², —P(═O)(R³)₂, —NR¹R², —C(O)YR²,—NR¹C(O)YR², —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R². Inanother subclass of interest, are compounds of the above embodiment inwhich R^(c) is H, halo, an aryl, heteroaryl, alkyl or heterocyclyl. Nonlimiting examples of R^(c) are H, —(CH₂)_(y)C(═O)NR¹R²,—(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R², —(CH₂)_(y)heterocyclyl,—(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, NH-aryl, NH-heteroaryl andNH-heterocyclyl; in which y is 0, 1, 2, 3 or 4 and alkyl includestraight (i.e. unbranched or acyclic), branched and cyclic alkyl groupsand alkyl, aryl, heteroaryl, heterocyclyl groups are optionallysubstituted.

Illustrative non limiting examples of such compounds include compoundsof any of the above Formulae in which Ring C is a triazole of thefollowing formulae:

In another embodiment, Ring C is a pyrazole of the following formulae:

In another embodiment, Ring C is a tetrazole of the following formulae:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

In another aspect of the previous embodiment, Ring C is a 5-memberedring heteroaryl comprising carbon atoms and 1-4 heteroatoms selectedfrom N and O, Non limiting examples are compounds of any of the aboveformulae in which Ring C is of the following type:

in which s is defined previously and the total number of substituentsR^(c) does not exceed the normal available valencies.

In a particular aspect of this embodiment, Ring C has the followingformulae:

in which Ring C is substituted with one or two R^(c) substituents.

R^(c) is as defined previously in part 1. Of additional interest is aclass of compounds as described above in which R^(c) is selected fromthe group consisting of —R¹, halo, —P(═O)(R³)₂, —OR², —NR¹R², —C(O)YR²,—NR¹C(O)YR², —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R². Inanother subclass of interest, are compounds of the above embodiment inwhich R^(c) is H, halo, NHC(O)R¹, NHC(O)NR¹R², C(O)NHR¹, C(O)NR¹R²,NR¹R², an aryl, heteroaryl, substituted alkyl or heterocyclyl. Nonlimiting examples of R^(c) are —(CH₂)_(y)C(═O)NR¹R²,—(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R², —(CH₂)_(y)OR²,—(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, NH-aryl,NH-heteroaryl and NH-heterocyclyl,

—(CH₂)_(m)P(═O)(alkyl)₂; in which y and m are independently selectedfrom 0, 1, 2, 3 and 4 and alkyl include straight (i.e. unbranched oracyclic), branched and cyclic alkyl groups and alkyl, aryl, heteroaryl,heterocyclyl groups are optionally substituted.

Non-limiting examples of this class include compounds of any of theabove formulae in which Ring C is:

Specific, non-limiting illustrative examples of this class includecompounds of any of the above formulae in which substituted Ring C is ofthe following formulae:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

In another specific embodiment, Ring C is a 5-membered heteroarylcomprising carbon atoms and 1-3 heteroatoms selected from N and S.

in which s is defined previously and the total number of substituentsR^(c) does not exceed the normal available valencies.

Of particular interest is a class of compounds as described above inwhich R^(c) is selected from the group consisting of —R¹, halo,—P(═O)(R³)₂, —OR², —NR¹R², —C(O)YR², —NR¹C(O)YR², —NR¹SO₂R²,—S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R². In another subclass ofinterest, are compounds of the above embodiment in which R^(c) is H,halo, —NHC(O)R¹, —C(O)NHR¹, —C(O)NR¹R², —NHC(O)NHR¹, —NR¹R², an aryl,heteroaryl, substituted alkyl or heterocyclyl. Non limiting examples ofR^(c) are —(CH₂)_(y)C(═O)NR¹R², —(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R²,—(CH₂)_(y)OR², —SO₂NR¹R², —(CH₂)_(y)SR², —CH₂)_(y)heterocyclyl,—(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, NH-aryl, NH-heteroaryl,NH-heterocyclyl and —(CH₂)_(m)P(═O)(alkyl)₂; in which y and m areindependently selected from 0, 1, 2, 3 and 4 and alkyl include straight(i.e. unbranched or acyclic), branched and cyclic alkyl groups andalkyl, aryl, heteroaryl, heterocyclyl groups are optionally substituted.

Non-limiting examples of this class include compounds of any of theabove formulae in which Ring C is:

Specific, non-limiting illustrative examples of this class includecompounds of any of the above formulae in which substituted Ring C is ofthe following formulae:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

Other non-limiting examples include compounds of any of the aboveformulae in which Ring C is furan or thiofuran:

in which s is defined previously and the total number of substituentsR^(c) does not exceed the normal available valencies.

Specific, non-limiting illustrative examples of this class includecompounds of any of the above formulae in which substituted Ring C is ofthe following formulae:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

In another embodiment, Ring C is a 6-membered heteroaryl ring.

In one aspect of this embodiment, Ring C is a pyrimidine of thefollowing types:

in which s is as previously described and the total number ofsubstituents R^(c) does not exceed the normal available valencies.

Of particular interest is a class of compounds as described above inwhich R^(c) is selected from the group consisting of —R¹, halo,—P(═O)(R³)₂, —OR², —NR¹R², —C(O)YR², —NR¹C(O)YR², —NR¹SO₂R²,—S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R². In another subclass ofinterest, are compounds of the above embodiment in which R^(c) is H,halo, NHC(O)R¹, NHC(O)NHR¹, C(O)NHR¹, C(O)NR¹R², NR¹R², an aryl,heteroaryl, substituted alkyl or heterocyclyl. Non limiting examples ofR^(c) are H, halo, —OCH₂CH₂NR¹R², —OCH₂C(O)NR¹R², —NR¹C(O)NR¹R²,—(CH₂)_(y)C(═O)NR¹R², —(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R²,—(CH₂)_(y)OR², —SO₂NR¹R², —SO₂R², (CH₂)_(y)SR², —(CH₂)_(y)heterocyclyl,—(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, NH-aryl, NH-heteroaryl,NH-heterocyclyl and —(CH₂)_(m)P(═O)(alkyl)₂; in which y and m areindependently selected from 0, 1, 2, 3 and 4 and alkyl include straight(i.e. unbranched or acyclic), branched and cyclic alkyl groups andalkyl, aryl, heteroaryl, heterocyclyl groups are optionally substituted.

Non-limiting examples of this class are compounds of any of the aboveformulae in which Ring C is:

Specific, non-limiting illustrative examples of this class includecompounds of any of the above formulae in which substituted Ring C is ofthe following formulae:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

In another embodiment, Ring C is a pyridine substituted with 1-4 R^(c).Of particular interest is a class of compounds as described above inwhich R^(c) is selected from the group consisting of —R¹, halo,—P(═O)(R³)₂, —OR², —NR¹R², —NR¹C(O)R², —NR¹SO₂R², —SO₂NR¹R² and SO₂R².In another subclass of interest, are compounds of the above embodimentin which R^(c) is H, halo, —NHC(O)R², —NR¹R⁴, an aryl, heteroaryl,substituted alkyl or heterocyclyl. Non limiting examples of R^(c) are H,—(CH₂)_(y)C(═O)NR¹R², —(CH₂)_(y)C(═O)aryl, —(CH₂)_(y)C(═O)heteroaryl,—(CH₂)_(y)C(═O)heterocyclyl, —(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R²,—(CH₂)_(y)OR², —(CH₂)_(y)S(O)R², —(CH₂)_(y)S(O)NR¹R²,—(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, NH-aryl,NH-heteroaryl, NH-heterocyclyl and —(CH₂)_(m)P(═O)(alkyl)₂, in which yand m are independently selected from 0, 1, 2, 3 and 4; and alkylinclude straight (i.e. unbranched or acyclic), branched and cyclic alkylgroups and alkyl, aryl, heteroaryl, heterocyclyl groups are optionallysubstituted.

Non-limiting examples of this class are compounds of any of the aboveformulae in which Ring C is:

Specific, non-limiting illustrative examples of this class includecompounds of any of the above formulae in which substituted Ring C is ofthe following formulae:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

In another embodiment, Ring C is a pyrazine substituted with 1-3 R^(c):Non-limiting examples of this class of compounds in which Ring C is:

Specific, non-limiting illustrative examples of this class includecompounds of any of the above formulae in which substituted Ring C is ofthe following formulae:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

In another embodiment, Ring C is a triazine substituted with 1 to 2R^(c) groups. Examples include compounds in which Ring C has thefollowing formulae:

in which s is defined previously and the number of substituents R^(c)does not exceed the maximum available valencies, which in the triazinecase s is 0, 1 or 2.

In one embodiment, two R^(c) groups form with the atoms to which theyare attached, a 5- or 6- or 7-membered saturated, partially saturated orunsaturated ring, which contains 0-4 heteroatoms selected from N, O,P(O) and S(O)_(r); and the resulting fused ring system is optionallysubstituted. Non-Limiting examples include compounds of all the aboveFormulae or of all classes and subclasses of this invention in whichRing C has the following formulae:

and the depicted fused ring systems are optionally substituted with R,which is selected from the group consisting of halo, —CN, —NO₂, —R¹,—OR², —O—NR¹R², —NR¹R², —NR¹—NR¹R², —NR¹—OR², —C(O)YR², —OC(O)YR²,—NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═Os)YR²,—YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR², —YP(═O)(YR³)(YR³),—Si(R³)₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and —NR¹SO₂NR¹R², in whichR¹, R², R³, Y and r are previously defined.

Additionally the depicted hydrogen of these fused ring system can alsobe replaced by a R group; or the nitrogen bearing the depicted hydrogencan be the point of attachment to the core molecule (i.e the nitrogen isattached to Ring A and the depicted hydrogen is therefore absent).

Specific, non-limiting illustrative examples of this class includecompounds of all the above formulae or of any other classes andsubclasses of this invention, in which substituted Ring C is of thefollowing formulae:

Non-limiting Illustrative examples of this class are compounds of thefollowing formulae:

For the previously described classes and subclasses of compounds, as inall compounds of the invention, L¹, Ring D and R^(d) are defined as inpart 1.

In some embodiment, Ring D is a phenyl substituted with 1-5 R^(d). Inone embodiment of interest R^(d) is selected from H, optionallysubstituted alkyl (such as for example CF₃) and halo.

In some other embodiment, Ring D is a 6-membered ring heteroaryl.Examples of this class are compounds of the above classes and subclassesin which Ring D is a pyridine, pyrazine, pyridazine, pyrimidine ortriazine.

In other embodiment, Ring D is a 5-membered ring heteroaryl. Examples ofthis class are compounds of the above classes and subclasses in whichRing D is imidazole, pyrazole, tetrazole, oxazole, thiazole, isoxazole,pyrolle, and the like.

Of particular interest is a class of compounds as described above inwhich R^(d) is selected from the group consisting of halo, —R¹, —OR²,—NR¹R², —NR¹C(O)R², —NR¹C(O)NR², C(O)NR¹R², C(O)OR¹, —SO₂NR¹R², —SO₂R¹,—NR¹SO₂R². In another subclass of interest, are compounds of the aboveembodiment in which R^(d) is H, alkyl, alkynyl, halo, aryl, heteroaryl,heterocyclyl, O-alkyl (i.e: OMe and the like), —CN, —C(O)NH-alkyl,—C(O)NH-aryl, C(O)NH-heterocyclyl, OH, —NR¹R², NHS(O)₂-alkyl,NHS(O)₂-aryl. Non limiting examples of R^(d) are H, F, Cl, CF₃, OCF₃,—(CH₂)_(y)C(═O)NR¹R², —(CH₂)_(y)C(═O)aryl, —SO₂NR¹R², NHSO₂R¹, loweralkyl, —(CH₂)_(y)C(═O)heteroaryl, —(CH₂)_(y)C(═O)heterocyclyl,—(CH₂)_(y)NHC(═O)R², —(CH₂)_(y)NR¹R², —(CH₂)_(y)OR², —(CH₂)_(y)SR²,—(CH₂)_(y)heterocyclyl, —(CH₂)_(y)aryl, —(CH₂)_(y)heteroaryl, NH-aryl,NH-heteroaryl, NH-heterocyclyl, in which y and m are independentlyselected from 0, 1, 2, 3 and 4; and alkyl include straight (i.e.unbranched or acyclic), branched and cyclic alkyl groups and alkyl,aryl, heteroaryl, heterocyclyl groups are optionally substituted.

Of special interest for use in this invention are compounds of formula Iin which Ring A is a pyridine; Ring B is a pyrolle; Ring C is attachedto position 2 of Ring A and Ring C is an optionally substituted phenylring. This class of compounds is illustrated by compounds of Formula VI.

In one aspect of this embodiment, are compounds of Formula VI in which Xis O. In another embodiment of interest X is NR⁴, such as for example NHand NCH₃.

In one embodiment are compounds of Formula VI in which Ring D is anoptionally substituted 5-membered heteroaryl ring.

In another embodiment are compounds of Formula VI in which Ring D is anoptionally substituted 6-membered heteroaryl ring.

In another embodiment are compounds of Formula VI in which Ring D is anoptionally substituted phenyl ring.

Of further interest are compounds of Formula VI and other subclassespreviously described in which X is O, L¹ is CR³R⁴ such as CH₂ or CHCH₃and the like. Of particular interest are compounds of Formula VI inwhich L¹ is CH₂.

Of further interest are compounds of Formula VI in which R^(c) group(s)are independently selected from H, alkyl, heterocyclyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, S(O)₂alkyl,S(O)₂NH-alkyl, C(O)NH₂, C(O)NH-alkyl, C(O)N(alkyl)₂, NH₂,NHS(O)₂-phenyl, NHCH₂aryl, NHCH₂heteroaryl or alkoxy in which eachalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted; andR^(d) group(s) are independently selected from H, lower alkyl (i.emethyl, ethyl, propyl, isopropyl and the like), CF₃ and halo (i.e Cl, Fand Br).

Of other special interest for use in this invention are compounds offormula I in which Ring A is a pyridine; Ring B is a pyrolle; Ring C isattached to position 2 of Ring A and Ring C is an optionally substitutedpyrazole ring. This class of compounds is illustrated by compounds ofFormula VII.

In one aspect of this embodiment, are compounds of Formula VII in whichX is O. In another embodiment of interest X is NR⁴, such as for exampleNH and NCH₃.

In one embodiment are compounds of Formula VII in which Ring D is anoptionally substituted 5-membered heteroaryl ring.

In another embodiment are compounds of Formula VII in which Ring D is anoptionally substituted 6-membered heteroaryl ring.

In another embodiment are compounds of Formula VII in which Ring D is anoptionally substituted phenyl ring.

Of further interest are compounds of Formula VII and other subclassespreviously described in which X is O, L¹ is CR³R⁴ such as CH₂ or CHCH₃and the like. Of particular interest are compounds of Formula VII inwhich L¹ is CH₂.

Of further interest are compounds of formulae VI or VII in which R^(c)group(s) are independently selected from H, alkyl, heterocyclyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, S(O)₂alkyl,S(O)₂NH-alkyl, C(O)NH₂, C(O)NH-alkyl, C(O)N(alkyl)₂ in which each alkyl,aryl, heterocyclyl and heteroaryl are optionally substituted; and R^(d)group(s) are independently selected from H, lower alkyl (i.e methyl,ethyl, propyl, isopropyl and the like), CF₃ and halo (i.e Cl, F and Br).Or further interest are compound of Formulae VI or VII in which p is 0,1, 2 or 3 and each R^(d) is independently selected from halo and CF₃ ands is 0 or 1 and R^(c) is halo, alkyl, aryl, arylalkyl, heteroaryl,heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl.

Of other special interest for use in this invention are compounds offormula I in which Ring A is a pyridine and Ring C is attached toposition 2 of Ring A. Illustrative, non-limiting examples of thissubclass are compounds of the following formulae:

in which Rings C and D; substituents R^(a), R^(c) and R^(d); linker Xand L¹; and variables s, n and p are as previously defined in part 1. Offurther interest are compounds of this class in which Ring C is anoptionally substituted phenyl or an optionally substituted pyrazole andRing D is an optionally substituted phenyl. Of one particular interestare compounds of these classes in which X is O and L¹ is CH₂ or CH(CH₃).Of other interest are compounds of these classes in which X is NH orNCH₃ and L¹ is C(O), CH₂ or CH(CH₃).

Of other special interest for use in this invention are compounds offormula I in which Ring B is a pyrolle. Illustrative, non-limitingexamples of this subclass are compounds of the following formulae:

in which Rings C and D; substituents R^(a), R^(c) and R^(d); linker Xand L¹; and variables s, n and p are as previously defined in part 1.

Of further interest are compounds of this class in which Ring C is anoptionally substituted phenyl or an optionally substituted pyrazole andRing D is an optionally substituted phenyl. Of one particular interestare compounds of these classes in which X is O and L¹ is CH₂ or CH(CH₃).Of other interest are compounds of these classes in which X is NH orNCH₃ and L¹ is C(O), CH₂ or CH(CH₃).

Other compounds of interest include among others, compounds of formulaeI to VII and of all the previous classes and subclasses in which R^(d)is selected from H, halo (i.e Chloro, Fluoro, Bromo), CF₃, optionallysubstituted lower alkyl group (i.e Methyl, Ethyl, Isopropyl, Cyclopropyland the like), CN, optionally substituted acetylene, NO₂, O-alkyl,S-alkyl, C(═O)alkyl, NH-alkyl, C(═O)NH(alkyl) and C(═O)N(alkyl)₂. Offurther interest are compounds of this class in which R^(d) is halo orCF³.

Other compounds of interest include among others, compounds of formulaeI to VII and of all previous classes and subclasses in which R^(c) isselected from H, halo, —CN, NR¹R², C(O)NR¹R², NR¹C(O)R², SO₂NR¹R², OR¹,—NO₂ and —R¹. Of further interest are compounds of this class in whichR^(c) is SO₂NH₂, SO₂NH(alkyl), SO₂N(alkyl)₂, O-alkyl, S-alkyl,C(═O)alkyl, NH₂, NH-alkyl, N(Alkyl)₂, C(O)NH₂, C(═O)NH(alkyl) orC(═O)N(alkyl)₂; in which the aryl, heteroaryl, heterocyclyl and alkylmoieties are optionally substituted.

Other compound of interest include among others, compounds of Formulae Ito VII in which R^(a) is selected from H, lower alkyl and halo.

Compounds of this invention of particular interest include those with onor more of the following characteristics:

-   -   a molecular weight of less than 1000, preferably less than 750        and more preferably less than 600 mass units (not including the        weight of any solvating or co-crystallizing species, of any        counter-ion in the case of a salt); or    -   inhibitory activity against a wild type or mutant (especially a        clinically relevant mutant) kinase, especially a kinase such as        Alk, Met, Jak2, bRaf, EGFR, Tie-2, FLT3 or another kinase of        interest with an IC₅₀ value of 1 μM or less (as determined using        any scientifically acceptable kinase inhibition assay),        preferably with an IC₅₀ of 500 nM or better, and optimally with        an IC₅₀ value of 250 nM or better; or    -   inhibitory activity against a given kinase with an IC50 value at        least 100-fold lower than their IC₅₀ values for other kinases of        interest; or    -   inhibitory activity for Alk, Met, Jak2 or B-Raf with a 1 μM or        better IC₅₀ value against each; or    -   a cytotoxic or growth inhibitory effect on cancer cell lines        maintained in vitro, or in animal studies using a scientifically        acceptable cancer cell xenograft model, (especially preferred        are compounds of the invention which inhibit proliferation of        Ba/F3 NMP-ALK, Ba/F3 EML4-ALK, Karpas 299 and/or SU-DHL-1 cells        with a potency at least as great as the potency of known alk        inhibitors such as NVP-TAE684 and PF2341066 among others,        preferably with a potency at least twice that of known alk        inhibitors, and more preferably with a potency at least 10 times        that of known alk inhibitors as determined by comparative        studies.

Also provided is a composition comprising at least one compound of theinvention or a salt, hydrate or other solvate thereof, and at least onepharmaceutically acceptable excipient or additive. Such compositions canbe administered to a subject in need thereof to inhibit the growth,development and/or metastasis of cancers, including solid tumors (e.g.,prostate cancer, colon cancer, pancreatic and ovarian cancers, breastcancer, non small cell lung cancer (NSCLS), neural tumors such asglioblastomas and neuroblastomas; esophaegeal carcinomas, soft tissuecancers such as rhabdomyosarcomas; among others); various forms oflymphoma such as a non-Hodgkin's lymphoma (NHL) known as anaplasticlarge-cell lymphoma (ALCL), various forms of leukemia such as chronicmyeloid leukemia (CML), acute myeloid leukemia (AML), acutelymphoblastic leukemia (ALL); and including cancers which are resistantto other treatment, including those which are resistant to treatmentwith another kinase inhibitor, and generally for the treatment andprophylaxis of diseases or undesirable conditions mediated by one ormore kinases which are inhibited by a compound of this invention.

The cancer treatment method of this invention involves administering (asa monotherapy or in combination with one or more other anti-canceragents, one or more agents for ameliorating side effects, radiation,etc) a therapeutically effective amount of a compound of the inventionto a human or animal in need of it in order to inhibit, slow or reversethe growth, development or spread of cancer, including solid tumors orother forms of cancer such as leukemias, in the recipient. Suchadministration constitutes a method for the treatment or prophylaxis ofdiseases mediated by one or more kinases inhibited by one of thedisclosed compounds or a pharmaceutically acceptable derivative thereof.“Administration” of a compound of this invention encompasses thedelivery to a recipient of a compound of the sort described herein, or aprodrug or other pharmaceutically acceptable derivative thereof, usingany suitable formulation or route of administration, as discussedherein. Typically the compound is administered one or more times permonth, often one or more times per week, e.g. daily, every other day, 5days/week, etc. Oral and intravenous administrations are of particularcurrent interest.

The phrase, “pharmaceutically acceptable derivative”, as used herein,denotes any pharmaceutically acceptable salt, ester, or salt of suchester, of such compound, or any other adduct or derivative which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound as otherwise described herein, or a metabolite orresidue (MW>300) thereof. Pharmaceutically acceptable derivatives thusinclude among others pro-drugs. A pro-drug is a derivative of acompound, usually with significantly reduced pharmacological activity,which contains an additional moiety which is susceptible to removal invivo yielding the parent molecule as the pharmacologically activespecies. An example of a pro-drug is an ester which is cleaved in vivoto yield a compound of interest. Pro-drugs of a variety of compounds,and materials and methods for derivatizing the parent compounds tocreate the pro-drugs, are known and may be adapted to the presentinvention.

Particularly favored derivatives and prodrugs of a parent compound arethose derivatives and prodrugs that increase the bioavailability of thecompound when administered to a mammal (e.g., by permitting enhancedabsorption into the blood following oral administration) or whichenhance delivery to a biological compartment of interest (e.g., thebrain or lymphatic system) relative to the parent compound. Preferredprodrugs include derivatives of a compound of this invention withenhanced aqueous solubility or active transport through the gutmembrane, relative to the parent compound.

One important aspect of this invention is a method for treating cancerin a subject in need thereof, which comprises administering to thesubject a treatment effective amount of a composition containing acompound of this invention. Treatment may be provided in combinationwith one or more other cancer therapies, include surgery, radiotherapy(e.g., gamma-radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes, etc.), endocrine therapy, biologic response modifiers (e.g.,interferons, interleukins, and tumor necrosis factor (TNF) to name afew), hyperthermia, cryotherapy, agents to attenuate any adverse effects(e.g., antiemetics), and other cancer chemotherapeutic drugs. The otheragent(s) may be administered using a formulation, route ofadministration and dosing schedule the same or different from that usedwith the compound of this invention.

Such other drugs include but not limited to one or more of thefollowing: an anti-cancer alkylating or intercalating agent (e.g.,mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, andIfosfamide); antimetabolite (e.g., Methotrexate); purine antagonist orpyrimidine antagonist (e.g., 6-Mercaptopurine, 5-Fluorouracil,Cytarabile, and Gemcitabine); spindle poison (e.g., Vinblastine,Vincristine, Vinorelbine and Paclitaxel); podophyllotoxin (e.g.,Etoposide, Irinotecan, Topotecan); antibiotic (e.g., Doxorubicin,Bleomycin and Mitomycin); nitrosourea (e.g., Carmustine, Lomustine);inorganic ion (e.g., Cisplatin, Carboplatin, Oxaliplatin or oxiplatin);enzyme (e.g., Asparaginase); hormone (e.g., Tamoxifen, Leuprolide,Flutamide and Megestrol); mTOR inhibitor (e.g., Sirolimus (rapamycin),Temsirolimus (CCI779), Everolimus (RAD001), AP23573 or other compoundsdisclosed in U.S. Pat. No. 7,091,213); proteasome inhibitor (such asVelcade, another proteasome inhibitor (see e.g., WO 02/096933) oranother NF-kB inhibitor, including, e.g., an IkK inhibitor); otherkinase inhibitors (e.g., an inhibitor of Src, BRC/Abl, kdr, flt3,aurora-2, glycogen synthase kinase 3 (“GSK-3”), EGF-R kinase (e.g.,Iressa, Tarceva, etc.), VEGF-R kinase, PDGF-R kinase, etc); an antibody,soluble receptor or other receptor antagonist against a receptor orhormone implicated in a cancer (including receptors such as EGFR, ErbB2,VEGFR, PDGFR, and IGF-R; and agents such as Herceptin, Avastin, Erbitux,etc.); etc. For a more comprehensive discussion of updated cancertherapies see, http://www.nci.nih.gov/, a list of the FDA approvedoncology drugs at http://www.fda.gov/cder/cancer/druglistframe.htm, andThe Merck Manual, Seventeenth Ed. 1999, the entire contents of which arehereby incorporated by reference. Examples of other therapeutic agentsare noted elsewhere herein and include among others, Zyloprim,alemtuzmab, altretamine, amifostine, nastrozole, antibodies againstprostate-specific membrane antigen (such as MLN-591, MLN591RL andMLN2704), arsenic trioxide, bexarotene, bleomycin, busulfan,capecitabine, Gliadel Wafer, celecoxib, chlorambucil,cisplatin-epinephrine gel, cladribine, cytarabine liposomal,daunorubicin liposomal, daunorubicin, daunomycin, dexrazoxane,docetaxel, doxorubicin, Elliott's B Solution, epirubicin, estramustine,etoposide phosphate, etoposide, exemestane, fludarabine, 5-FU,fulvestrant, gemcitabine, gemtuzumab-ozogamicin, goserelin acetate,hydroxyurea, idarubicin, idarubicin, Idamycin, ifosfamide, imatinibmesylate, irinotecan (or other topoisomerase inhibitor, includingantibodies such as MLN576 (XR11576)), letrozole, leucovorin, leucovorinlevamisole, liposomal daunorubicin, melphalan, L-PAM, mesna,methotrexate, methoxsalen, mitomycin C, mitoxantrone, MLN518 or MLN608(or other inhibitors of the flt-3 receptor tyrosine kinase, PDFG-R orc-kit), itoxantrone, paclitaxel, Pegademase, pentostatin, porfimersodium, Rituximab (RITUXAN®), talc, tamoxifen, temozolamide, teniposide,VM-26, topotecan, toremifene, 2C4 (or other antibody which interfereswith HER2-mediated signaling), tretinoin, ATRA, vairubicin, vinorelbine,or pamidronate, zoledronate or another bisphosphonate.

This invention further comprises the preparation of a compound of any ofFormulae I, II, III, IV, IVA, IVB, V, VA, VB, VI, VII or of any otherclasses and subclasses of compounds of this invention.

The invention also comprises the use of a compound of the invention, ora pharmaceutically acceptable derivative thereof, in the manufacture ofa medicament for the treatment either acutely or chronically of cancer(including lymphoma and solid tumors, primary or metastatic, includingcancers such as noted elsewhere herein and including cancers which areresistant or refractory to one or more other therapies). The compoundsof this invention are useful in the manufacture of an anti-cancermedicament. The compounds of the present invention are also useful inthe manufacture of a medicament to attenuate or prevent disordersthrough inhibition of one or more kinases such as ALK, jak2, b-raf, met,Tie-2, EGFR, FLT3, FAK, Pim-1, P13k, etc. . . . .

This invention further encompasses a composition comprising a compoundof the invention, including a compound of any of the described classesor subclasses, including those of any of the formulas noted above, amongothers, preferably in a therapeutically-effective amount, in associationwith a least one pharmaceutically acceptable carrier, adjuvant ordiluent.

Compounds of this invention are also useful as standards and reagentsfor characterizing various kinases, especially but not limited to ALK,Met, Jak2, b-Raf, Tie-2, EGFR, FLT3 among others as well as for studyingthe role of such kinases in biological and pathological phenomena; forstudying intracellular signal transduction pathways mediated by suchkinases, for the comparative evaluation of new kinase inhibitors; andfor studying various cancers in cell lines and animal models.

3. Definitions

In reading this document, the following information and definitionsapply unless otherwise indicated.

The term “Alkyl” is intended to include linear (i.e., unbranched oracyclic), branched, cyclic, or polycyclic non aromatic hydrocarbongroups, which are optionally substituted with one or more functionalgroups. Unless otherwise specified, “alkyl” groups contain one to eight,and preferably one to six carbon atoms. C₁₋₆ alkyl is intended toinclude C₁, C₂, C₃, C₄, C₅, and C₆ alkyl groups. Lower alkyl refers toalkyl groups containing 1 to 6 carbon atoms. Examples of Alkyl include,but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyltert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, etc. Alkyl may besubstituted or unsubstituted. Illustrative substituted alkyl groupsinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl,substituted phenethyl, etc.

The term “Alkoxy” represents a subset of alkyl in which an alkyl groupas defined above with the indicated number of carbons attached throughan oxygen bridge. For example, “alkoxy” refers to groups —O-alkyl,wherein the alkyl group contains 1 to 8 carbons atoms of a linear,branched, cyclic configuration. Examples of “alkoxy” include, but arenot limited to, methoxy, ethoxy, n-propoxy, i-propoxy, t-butoxy,n-butoxy, s-pentoxy and the like.

“Haloalkyl” is intended to include both branched and linear chainsaturated hydrocarbon having one or more carbon substituted with aHalogen. Examples of haloalkyl, include, but are not limited to,trifluoromethyl, trichloromethyl, pentafluoroethyl and the like.

The term “alkenyl” is intended to include hydrocarbon chains of linear,branched, or cyclic configuration having one or more unsaturatedCarbon-carbon bonds that may occur in any stable point along the chainor cycle. Unless otherwise specified, “alkenyl” refers to groups usuallyhaving two to eight, often two to six carbon atoms. For example,“alkenyl” may refer to prop-2-enyl, but-2-enyl, but-3-enyl,2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, andthe like. Furthermore, alkenyl groups may be substituted orunsubstituted.

The term “alkynyl” is intended to include hydrocarbon chains of eitherlinear or branched configuration, having one or more carbon-carbontriple bond that may occur in any stable point along the chain. Unlessotherwise specified, “alkynyl” groups refer refers to groups having twoto eight, preferably two to six carbons. Examples of “alkynyl” include,but are not limited to prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl,3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc. Furthermore, alkynylgroups may be substituted or unsubstituted.

Cycloalkyl is a subset of alkyl and includes any stable cyclic orpolycyclic hydrocarbon groups of from 3 to 13 carbon atoms, any of whichis saturated. Examples of such cycloalkyl include, but are not limitedto cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane,and the like, which, as in the case of other alkyl moieties, mayoptionally be substituted. The term “cycloalkyl” may be usedinterchangeably with the term “carbocycle”.

Cycloalkenyl is a subset of alkenyl and includes any stable cyclic orpolycyclic hydrocarbon groups of from 3 to 13 carbon atoms, preferablyfrom 5 to 8 carbon atoms, which contains one or more unsaturatedcarbon-carbon double bonds that may occur in any point along the cycle.Examples of such cycloalkenyl include, but are not limited tocyclopentenyl, cyclohexenyl and the like.

Cycloalkynyl is a subset of alkynyl and includes any stable cyclic orpolycyclic hydrocarbon groups of from 5 to 13 carbon atoms, whichcontains one or more unsaturated carbon-carbon triple bonds that mayoccur in any point along the cycle. As in the case of other alkenyl andalkynyl moieties, cycloalkenyl and cycloalkynyl may optionally besubstituted.

“Heterocycle”, “heterocyclyl”, or “heterocyclic” as used herein refersto non-aromatic ring systems having five to fourteen ring atoms,preferably five to ten, in which one or more ring carbons, preferablyone to four, are each replaced by a heteroatom such as N, O, or S,Non-limiting examples of heterocyclic rings include3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl,3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl,2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl,benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl,benzothiolanyl, and benzothianyl. Also included within the scope of theterm “heterocyclyl” or “heterocyclic”, as it is used herein, is a groupin which a non-aromatic heteroatom-containing ring is fused to one ormore aromatic or non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving six to fourteen ring atoms, such as phenyl, 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. An “aryl” ring may contain oneor more substituents. The term “aryl” may be used interchangeably withthe term “aryl ring”. “Aryl” also includes fused polycyclic aromaticring systems in which an aromatic ring is fused to one or more rings.Non-limiting examples of useful aryl ring groups include phenyl,hydroxyphenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl,trialkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl, anthryl,phenanthro and the like, as well as 1-naphthyl, 2-naphthyl, 1-anthracyland 2-anthracyl. Also included within the scope of the term “aryl”, asit is used herein, is a group in which an aromatic ring is fused to oneor more non-aromatic rings, such as in a indanyl, phenanthridinyl, ortetrahydronaphthyl, where the radical or point of attachment is on thearomatic ring.

The term “heteroaryl” as used herein refers to stable heterocyclic, andpolyheterocyclic aromatic moieties having 5-14 ring atoms. Heteroarylgroups may be substituted or unsubstituted and may comprise one or morerings. Examples of typical heteroaryl rings include 5-memberedmonocyclic ring groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl,furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl and the like;6-membered monocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl and the like; and polycyclic heterocyclic ringgroups such as benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl,isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, benzothiazole,benzimidazole, tetrahydroquinoline cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, phenoxazinyl,and the like (see e.g. Katritzky, Handbook of Heterocyclic Chemistry).Further specific examples of heteroaryl rings include 2-furanyl,3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl,3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl,2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl,benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl,benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl,isoquinolinyl, indolyl, isoindolyl, acridinyl, or benzoisoxazolyl.Heteroaryl groups further include a group in which a heteroaromatic ringis fused to one or more aromatic or nonaromatic rings where the radicalor point of attachment is on the heteroaromatic ring. Examples includetetrahydroquinoline, tetrahydroisoquinoline, andpyrido[3,4-d]pyrimidinyl, imidazo[1,2-a]pyrimidyl,imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyiridinyl,imidazo[1,2-c]pyrimidyl, pyrazolo[1,5-a][1,3,5]triazinyl,pyrazolo[1,5-c]pyrimidyl, imidazo[1,2-b]pyridazinyl,imidazo[1,5-a]pyrimidyl, pyrazolo[1,5-b][1,2,4]triazine, quinolyl,isoquinolyl, quinoxalyl, imidazotriazinyl, pyrrolo[2,3-d]pyrimidyl,triazolopyrimidyl, pyridopyrazinyl. The term “heteroaryl” also refers torings that are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

An aryl group (including the aryl portion of an aralkyl, aralkoxy, oraryloxyalkyl moiety and the like) or heteroaryl group (including theheteroaryl portion of a heteroaralkyl or heteroarylalkoxy moiety and thelike) may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl or heteroarylgroup include halogen (F, Cl, Br or I), alkyl, alkenyl, alkynyl, —CN,—R¹, —OR², —S(O)_(r)R², (wherein r is an integer of 0, 1 or 2),—SO₂NR¹R², —NR¹R², —O—NR¹R², —NR¹—NR¹R², —(CO)YR², —O(CO)YR²,—NR¹(CO)YR², —S(CO)YR², —NR¹C(═S)YR², —OC(═S)YR², —C(═S)YR², whereineach occurrence of Y is independently —O—, —S—, or a chemical bond;—(CO)YR² thus encompasses —C(═O)R², —C(═O)OR², and —C(═O)NR¹R².Additional substituents include —YC(═NR¹)YR², —YC(═N—OR¹)YR²,—YC(═N—NR¹R²)YR², —COCOR², —COMCOR² (where M is a 1-6 carbon alkylgroup), —YP(═O)(YR³)(YR³) (including among others —P(═O)(R³)₂),—Si(R³)₃, —NO₂, —NR¹SO₂R² and —NR¹SO₂NR¹R². To illustrate further,substituents in which Y is —NR¹ thus include among others, —NR¹C(═O)R²,—NR¹C(═O)NR¹R², —NR¹C(═O)OR², and —NR¹C(═NH)NR¹R². R³ substituent isselected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, heterocyclyl; R¹ and R² substituents ateach occurrence are independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, heterocyclyl, and R¹, R² and R³ substituents may themselvesbe substituted or unsubstituted. Examples of substituents allowed on R¹,R² and R³ include, among others amino, alkylamino, dialkylamino,aminocarbonyl, halogen, alkyl, aryl, heteroaryl, carbocycle,heterocycle, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro, cyano, carboxy,alkoxycarbonyl, alkylcarbonyl, hydroxy, alkoxy, haloalkoxy groups.Additional illustrative examples include protected OH (such as acyloxy),phenyl, substituted phenyl, —O-phenyl, —O-(substituted) phenyl, -benzyl,substituted benzyl, —O-phenethyl (i.e., —OCH₂CH₂C₆H₅),—O-(substituted)phenethyl. Non-limiting illustrations of a substitutedR¹, R² or R³ moiety include haloalkyl and trihaloalkyl, alkoxyalkyl,halophenyl, -M-heteroaryl, -M-heterocycle, -M-aryl, -M-OR², -M-SR²,-M-NR¹R², -M-OC(O)NR¹R², -M-C(═NR²)NR¹R², -M-C(═NR¹)OR², -M-P(O)R³R³,Si(R³)₃, -M-NR¹C(O)R², -M-NR¹C(O)OR², -M-C(O)R², -M-C(═S)R²,-M-C(═S)NR¹R², -M-C(O)NR¹R², -M-C(O)NR²-M-NR¹R², -M-NR²C(NR¹)NR¹R²,-M-NR¹C(S)NR¹R², -M-S(O)₂R¹, -M-C(O)R¹, -M-OC(O)R¹, -MC(O)SR²,-M-S(O)₂NR¹R², —C(O)-M-C(O)R², -MCO₂R², -MC(═O)NR¹R², -M-C(═NH)NR¹R²,and -M-OC(═NH)NR¹R² (wherein M is a 1-6 carbon alkyl group).

Some more specific examples include but are not limited to chloromethyl,trichloromethyl, trifluoromethyl, methoxyethyl, alkoxyphenyl,halophenyl, —CH₂-aryl, —CH₂-heterocycle, —CH₂C(O)NH₂, —C(O)CH₂N(CH₃)₂,—CH₂CH₂OH, —CH₂OC(O)NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NEt₂, —CH₂OCH₃, —C(O)NH₂,—CH₂CH₂-heterocycle, —C(═S)CH₃, —C(═S)NH₂, —C(═NH)NH₂, —C(═NH)OEt,—C(O)NH-cyclopropyl, C(O)NHCH₂CH₂-heterocycle, —C(O)NHCH₂CH₂OCH₃,—C(O)CH₂CH₂NHCH₃, —CH₂CH₂F, —C(O)CH₂-heterocycle, —CH₂C(O)NHCH₃,—CH₂CH₂P(O)(CH₃)₂, Si(CH₃)₃ and the like.

An alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, cycloalkenyl,cycloalkynyl or non-aromatic heterocyclic group may thus also containone or more substituents. Examples of suitable substituents on suchgroups include, but are not limited to those listed above for the carbonatoms of an aryl or heteroaryl group and in addition include thefollowing substituents for a saturated carbon atom: ═O, ═S, ═NH,═NNR²R³, ═NNHC(O)R², ═NNHCO₂R², or ═NNHSO₂R², wherein R² and R³ at eachoccurrence are independently hydrogen, alkyl, alkenyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl.

Illustrative examples of substituents on an aliphatic, heteroaliphaticor heterocyclic group include amino, alkylamino, dialkylamino,aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, —CN,carboxy, alkoxycarbonyl, alkylcarbonyl, —OH, haloalkoxy, or haloalkylgroups.

Illustrative substituents on a nitrogen, e.g., in an heteroaryl ornon-aromatic heterocyclic ring include R¹, —NR¹R², —C(═O)R², —C(═O)OR²,—C(═O)SR², —C(═O)NR¹R², —C(═NR²)NR¹R², —C(═NR²)OR², —C(═NR¹)R³, —COCOR²,—COMCOR², —CN, —SO₂R², S(O)R², —P(═O)(YR³)(YR³), —NR¹SO₂R² and—NR¹SO₂NR¹R², wherein each occurrence of R³ is alkyl, alkenyl, alkynyl,cycloalkkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl andheterocyclyl; each occurrence of R¹ and R² is independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl and heterocyclyl.

When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl)is substituted with a number of substituents varying within an expresslydefined range, it is understood that the total number of substituentsdoes not exceed the normal available valencies under the existingconditions. Thus, for example, a phenyl ring substituted with “m”substituents (where “m” ranges from 0 to 5) can have 0 to 5substituents, whereas it is understood that a pyridinyl ring substitutedwith “m” substituents has a number of substituents ranging from 0 to 4.The maximum number of substituents that a group in the compounds of theinvention may have can be easily determined.

This invention encompasses only those combinations of substituents andvariables that result in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one that hasstability sufficient to permit its preparation and detection. Preferredcompounds of this invention are sufficiently stable that they are notsubstantially altered when kept at a temperature of 40° C. or less, inthe absence of moisture or other chemically reactive conditions, for atleast a week.

Certain compounds of this invention may exist in tautomeric forms, andthis invention includes all such tautomeric forms of those compoundsunless otherwise specified.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Thus, single stereochemicalisomers as well as enantiomeric and diastereomeric mixtures of thepresent compounds are within the scope of the invention. Thus, thisinvention encompasses each diasteriomer or enantiomer substantially freeof other isomers (>90%, and preferably >95%, free from otherstereoisomers on a molar basis) as well as a mixture of such isomers.

Particular optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another method involves synthesisof covalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound.

Optically active compounds of the invention can be obtained by usingactive starting materials. These isomers may be in the form of a freeacid, a free base, an ester or a salt.

The compounds of this invention can exist in radiolabelled form, i.e.,said compounds may contain one or more atoms containing an atomic massor mass number different from the atomic mass or mass number: ordinarilyfound in nature. Radioisotopes of hydrogen, carbon, phosphorous,fluorine and chlorine include ³H, ¹⁴C_(,) ³²P, ³⁵S, ⁴³F and ³⁶CI,respectively. Compounds of this invention which contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of this invention. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,radioisotopes are particularly preferred for their ease of preparationand detectability.

Radiolabelled compounds of this invention can generally be prepared bymethods well known to those skilled in the art. Conveniently, suchradiolabelled compounds can be prepared by carrying out the proceduresdisclosed herein except substituting a readily available radiolabelledreagent for a non-radiolabelled reagent.

4. Synthetic Overview

The practitioner has a well-established literature of heterocyclic andother relevant chemical transformations, recovery and purificationtechnologies to draw upon, in combination with the information containedin the examples which follow, for guidance on synthetic strategies,protecting groups, and other materials and methods useful for thesynthesis, recovery and characterization of the compounds of thisinvention, including compounds containing the various choices for theR^(a), R^(c), R^(d) and Rings A, B, C, D and linkers X and L¹.

Various synthetic approaches may be used to produce the compoundsdescribed herein, including those approaches depicted schematicallybelow. The practitioner will appreciate that protecting groups may beused in these approaches. “Protecting groups”, are moieties that areused to temporarily block chemical reaction at a potentially reactivesite (e.g., an amine, hydroxy, thiol, aldehyde, etc.) so that a reactioncan be carried out selectively at another site in a multifunctionalcompound. In preferred embodiments, a protecting group reactsselectively in good yield to give a protected substrate that is suitablefor the planned reactions; the protecting group should be selectivelyremovable in good yield by readily available, preferably nontoxicreagents that do not unduly attack the other functional groups present;the protecting group preferably forms an readily separable derivative(more preferably without the generation of new stereogenic centers); andthe protecting group preferably has a minimum of additionalfunctionality to avoid the complication of further sites of reaction. Awide variety of protecting groups and strategies, reagents andconditions for deploying and removing them are known in the art. See,e.g., “Protective Groups in Organic Synthesis” Third Ed. Greene, T. W.and Wuts, P. G., Eds., John Wiley & Sons, New York: 1999. For additionalbackground information on protecting group methodologies (materials,methods and strategies for protection and deprotection) and othersynthetic chemistry transformations useful in producing the compoundsdescribed herein, see in R. Larock, Comprehensive organicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons(1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995). The entire contents of these references are hereby incorporatedby reference.

Also, one may chose reagents enriched for a desired isotope, e.g.deuterium in place of hydrogen, to create compounds of this inventioncontaining such isotope(s). Compounds containing deuterium in place ofhydrogen in one or more locations, or containing various isotopes of C,N, P and O, are encompassed by this invention and may be used, forinstance, for studying metabolism and/or tissue distribution of thecompounds or to alter the rate or path of metabolism or other aspects ofbiological functioning.

The compounds of this invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or by a variation thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto those described below. The reactions are preformed in a solventappropriate to the reagents and materials employed and suitable for thetransformation being effected. It will be understood by those skilled inthe art of organic synthesis that the functionality present on themolecule should be consistent the transformations proposed. This willsometimes required some judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention.

A compound of the present invention could be prepared as outlined inScheme 1 to Scheme 17A and via standard methods known to those skilledin the art.

A compound of Formula I, II, IV, IVA, VI or VII can be prepared from5-bromo-2-chloro-3-nitropyridine as shown in Scheme 1.5-bromo-2-chloro-3-nitropyridine is first treated with sodium hydrideand diethyl propanedioate to generate intermediate 1a which consequentlyundergoes decarbonylation under acidic conditions to generate5-bromo-2-methyl-3-nitropyridine (intermediate 1b). Intermediate 1b istreated with N,N-dimethylacetamide in the presence ofN,N-dimethylformamide to generate intermediate 1c. Incomplete reductionwith SnCl₂ generate 6-bromo-1H-pyrrolo[3,2-b]pyridin-1-ol asintermediate 1d. The [Ring D]-L¹ moiety can then be incorporated bytreatment of intermediate 1d with a [Ring D]-L¹-Br compound or achemically equivalent compound in which the Bromide is replaced byanother halide (such as for example Iodide) or is replaced by otherleaving groups (such as for example a mesylate or the like), and thedisplacement can take place in the presence of a base such as forexample potassium carbonate in a suitable solvent (i.e.dimethylformamide and the like). A catalytic amount of potassium iodidecan be added to facilitate the displacement. The resulting intermediate1e is then submitted to Suzuki coupling conditions with a boronic acidor a boronic ester introducing therein the Ring C moiety.

An approach to the preparation of a compound of formula I, II, IV, IVAor VI is illustrated below in Scheme 1A in which L¹ is CH₂, Ring C andRing D are optionally substituted with 1 to 5 R^(c) and 1-5 R^(d)respectively.

An approach to the preparation of a compound of formula I, II, IV, WA orVI is illustrated below in Scheme 1A in which L¹ is a bond, Ring C andRing D are optionally substituted with 1 to 5 R^(c) and 1-5 R^(d)respectively.

A compound of Formula I, II, N, IVA, VI or VII in which L¹ is CH(CH₃)can be prepared from an optionally substituted 1-phenylethanone as shownin Scheme 2. The ketone is reduced to the corresponding secondaryalcohol using sodium borohydride and generating Intermediate 2a. Thealcohol 2a was activated by treatment with Mesyl chloride in thepresence of a base scavenger, such as for example triethyamine, andgenerated intermediate 2b. The mesylate 2b was displaced with6-bromo-1H-pyrrolo[3,2-b]pyridin-1-ol (intermediate 1d described inScheme 1) and generated intermediate 2c. Intermediate 2c is thensubmitted to Suzuki coupling conditions with a boronic acid or a boronicester introducing therein the [Ring C] moiety.

An approach to the preparation of a compound of Formula I, II, IV, IVAor VII in which L¹ is CHCH₃, is illustrated below in Scheme 2A in whichRing C is a substituted pyrazole, and Ring D is a tri-substitutedphenyl.

A compound of Formula I, III, IV, IVA, VI or VII in which X is NH and L¹is CH₂ can be prepared from 6-bromo-1H-pyrrolo[3,2-b]pyridine in 3steps. 6-bromo-1H-pyrrolo[3,2-b]pyridine is reacted with monochloraminein the presence of a base such as for example sodium hydride to generateintermediate 3a. Compound 3a is condensed with a [Ring D]CHO moiety. Theresulting imine 3b is reduced using a reducing agent such as NaBH₄ orLiAlH₄ generating compound 3c. Intermediate 3c is then submitted toSuzuki coupling conditions with a boronic acid or a boronic esterintroducing therein the [Ring C] moiety.

An approach to the preparation of a compound of Formula I, III, IV, IVAor VII in which X is NH and L¹ is CH₂, is illustrated below in Scheme 3Ain which Ring D is a substituted phenyl and Ring C is a substitutedpyrazole.

An alternative synthesis of compound of Formula I, III, IV, IVA, VI orVII in which X is NH and L¹ is CHCH₃ can be prepared from5-bromo-2-methyl-3-nitropyridine. The [Ring C] moiety is firstintroduced in a Suzuki coupling reaction generating compound 4a.Intermediate 4a is treated with N,N-dimethylacetamide in the presence ofdimethylformamide to generate intermediate 4b. Upon hydrogenationcondition, cyclization to 1H-pyrrolo[3,2-b]pyridine occurred generatingintermediate 4c. Conversion to the final product can be carried out in a3 step synthesis as described in Scheme 3.

An approach to the preparation of a few compounds of Formula I, III, IV,IVA or VII in which X is NH, L¹ is CH₂ is illustrated in Scheme 4A inwhich Ring D is an optionally substituted phenyl and Ring C is asubstituted pyrazole.

The substituted pyrazole boronic ester used in step 1 of Scheme 4A, wassynthesized from N-BOC protected piperidin-4-ol as described is Scheme4B.

A compound of Formula I, III, IV, IVA or VI in which X is NH and L¹ isCHCH₃ can be prepared from intermediate 4e (described in Scheme 4) inone step as illustrated in Scheme 5:

In a non limiting example Scheme 5A illustrates the synthesis of acompound of Formula I, III, IV or IVA in which X is NH and L¹ is CHCH₃,Ring D is a substituted phenyl and Ring C is a substituted pyrazole.

An alternative method for synthesizing a compound of Formula I, III, IV,IVA, VI or VII in which X is NH and L¹ is CHCH₃ is condensing anintermediate 4d (as described in Scheme 4) with a methyl ketone. Theresulting intermediate 6a is then reduced with a reducing agent such asfor example NaBH₄ or LiAlH₄ or the like.

In a non limiting example, Scheme 6A illustrates the synthesis of acompound of Formula I, III, IV, IVA or VII in which X is NH and L¹ isCHCH₃, Ring D is a substituted phenyl and Ring C is a substitutedpyrazole.

A compound of Formula I, III, IV, IVA, VI or VII in which X is NCH₃ andL¹ is CH₂ can be prepared from alkylation of a corresponding compound inwhich X is NH as shown in Scheme 7.

In a non limiting example, Scheme 7A illustrates the synthesis of acompound of Formula I, III, IV, IVA or VII in which X is NCH₃ and L¹ isCH₂, Ring D is a substituted phenyl and Ring C is a substitutedpyrazole.

A compound of Formula I, III, IV or IVA in which Ring B is pyrazole,Ring A is pyridine, X is NH and L¹ is CH₂ can be prepared as shown inScheme 7. Treatment of 5-Bromo-3-fluoropyridine-2-carboxaldehyde withhydrazine results in cyclization to 6-bromo-1H-pyrazolo[4,3-b]pyridine(intermediate 7a). A similar conversion was described in US applicationUS 2007/244178. Amination with monochloramine in the presence of sodiumhydride generates intermediate 7b. The amine functionality ofintermediate 7b is then condensed with an aldehyde generating the imine7c. Reduction of the imine is carried out with a reducing agent such asfor example sodium borohydride or lithium aluminium hydride providescompound 7d.

Ring C moiety is then introduced using Suzuki coupling conditions.

Alternatively, the Ring C moiety could be introduced via Suzuki couplingprior to the formation of the bicyclic core and prior to theintroduction of the Ring D moiety as illustrated in Scheme 9.

A compound of Formula I, III, IV, IVA, V or VA in which Ring B isimidazole, Ring A is pyridine or pyrazine, X is NH, L¹ is CH₂ can beprepared as shown in Scheme 10.

Alternatively, the Ring C moiety could be introduced via Suzuki couplingprior to the introduction of the Ring D moiety as illustrated in Scheme11.

A compound of Formula I, II, IV or IVA in which Ring B is a triazole,Ring A is pyridine, L¹ is CH₂ and X is O is described in Scheme 12.

Alternatively, the Ring C moiety could be introduced via Suzuki couplingprior to the introduction of the Ring D moiety as illustrated in Scheme13.

A compound of Formula I, II, IV or IVA in which Ring B is imidazole,Ring A is pyridine, L¹ is CH₂ and X is O is described in Scheme 14.

Alternatively, the Ring C moiety could be introduced via Suzuki couplingprior to the introduction of the Ring D moiety as illustrated in Scheme15.

A compound of Formula I, III, IV, IVA, VI or VII in which X is NH and L¹is C(O) can be prepared by treating an intermediate 4d (described inScheme 4) with an acid using standard amide coupling conditions such asfor example HBTU and triethylamine, as described in Scheme 16.

In a non limiting example, Scheme 16A illustrates the synthesis of acompound of Formula I, III, IV, IVA or VI in which X is NH and L¹ isC(O), Rings C and D are substituted phenyls.

A compound of Formula I, III, IV, IVA, VI or VII in which X is NH and L¹is a bond can be prepared by treating an intermediate 4d (described inScheme 4) with an aryl or heteroaryl halide in the presence of base suchas for example sodium carbonate, as described in Scheme 17.

In a non limiting example, Scheme 17A illustrates the synthesis of acompound of Formula I, III, IV, IVA or VI in which X is NH and L¹ is abond and Rings C and D are substituted phenyls.

The synthetic guidance provided in Schemes 1 through 17A is applicableto a variety of Rings A, B, C and D and linkers X and L¹ of thisinvention and allows the preparation of all compounds of this invention.

With synthetic approaches such as the foregoing, combined with theexamples which follow, additional information provided herein andconventional methods and materials, the practitioner should be able toprepare the full range of compounds disclosed herein.

5. Uses, Formulations, Administration Pharmaceutical Uses; Indications

This invention provides compounds having biological properties whichmake them of interest for treating or modulating disease in whichkinases may be involved, symptoms of such disease, or the effect ofother physiological events mediated by kinases. For instance, a numberof compounds of this invention have been shown to inhibit tyrosinekinase activity of alk, fak and c-met, among other tyrosine kinaseswhich are believed to mediate the growth, development and/or metastasisof cancer. A number of compounds of the invention have also been foundto possess potent in vitro activity against cancer cell lines, includingamong others karpas 299 cells. Such compounds are thus of interest forthe treatment of cancers, including solid tumors as well as lymphomasand including cancers which are resistant to other therapies.

Such cancers include, among others, cancers of the breast, non smallcell lung cancer (NSCLS), neural tumors such as glioblastomas andneuroblastomas; esophaegeal carcinomas, soft tissue cancers such asrhabdomyosarcomas, among others); various forms of lymphoma such as anon-Hodgkin's lymphoma (NHL) known as anaplastic large-cell lymphoma(ALCL), various forms of leukemia such as chronic myeloid leukemia(CML), acute myeloid leukemia (ALL); and including cancers which are ALKor c-met mediated.

Anaplastic Lymphoma Kinase (ALK) is a cell membrane-spanning receptortyrosine kinase, which belong to the insulin receptor subfamily. ALKreceptor tyrosine kinase (RTK) was initially identified due to itsinvolvement in the human non-Hodgkin lymphoma subtype known asanaplastic large-cell lymphoma (ALCL). ALK normally has a restricteddistribution in mammalian cells, being found at significant levels onlyin nervous system during embryonic development, suggesting a possiblerole for ALK in brain development (Duyster, J. Et al., Oncogene, 2001,20, 5623-5637).

In addition to its role in normal development, expression of thefull-length normal ALK has also been detected in cell lines derived froma variety of tumors such as neuroblastomas, neuroectodermal tumors(Lamant L. Et al., Am. J. Pathol., 2000, 156, 1711-1721;Osajima-Hakomori Y., et al., Am. J. Pathol. 2005, 167, 213-222) andglioblastoma (Powers C. et al., J. Biol. Chem. 2002, 277, 14153-14158;Grzelinski M. et al., Int. J. Cancer, 2005, 117, 942-951; Mentlein, R.Et al., J. Neurochem., 2002, 83, 747-753) as well as breast cancer andmelanoma lines (Dirk W G. Et al., Int. J. Cancer, 2002, 100, 49-56).

In common with other RTKs, translocations affect the ALK gene, resultingin expression of oncogenic fusion kinases—the most common of which isNPM-ALK. For example, approximately sixty percent of anaplastic largecell lymphomas (ALCL) are associated with a chromosome mutation thatgenerates a fusion protein consisting of nucleophosmin (NMP) and theintracellular domain of ALK. (Armitage, J. O. et al., Cancer: principleand practice of oncology, 6^(th) Edition, 2001, 2256-2316; kutok, J. L.& Aster J. C., J. Clin. Oncol., 2002, 20, 3691-3702; Wan, W. et al.,Blood, 2006, 107, 1617-1623. This mutant protein, NMP-ALK, possesses aconstitutively active tyrosine kinase domain that is responsible for itsoncogenic property through activation of downstream effectors (Falini, Band al., Blood, 1999, 94, 3509-3515; Morris, S. W. et al., Brit. J.Haematol., 2001, 113, 275-295). Experimental data have demonstrated thatthe aberrant expression of constitutuvely active ALK is directlyimplicated in the pathogenesis of ALCL and that inhibition of ALK canmarkedly impair the growth of ALK positive lymphoma cells (Kuefer, Mu etal., Blood, 1997, 90, 2901-2910; Bai, R. Y. et al., Exp. Hematol., 2001,29, 1082-1090; Slupianek, A. et al., Cancer Res., 2001, 61, 2194-2199;Turturro, F. et al., Clin. Cancer. Res., 2002, 8, 240-245). Theconstitutively activated chimeric ALK has also been demonstrated inabout 60% of inflammatory myofibroblastic tumors (IMTs), a slow growingsarcoma that mainly affects children and young adults (Lawrence, B. etal., Am. J. Pathol., 2000, 157, 377-384). Furthermore, recent reportshave also described the occurrence of a variant ALK fusion, TPM4-ALK, incases of squamous cell carcinoma (SCC) of the esophagus (Jazzi fr., etal., World J. Gastroenterol., 2006, 12, 7104-7112; Du X., et al., J.Mol. Med., 2007, 85, 863-875; Aklilu M., Semin. Radiat. Oncol., 2007,17, 62-69). Thus, ALK is one of the few examples of an RTK implicated inoncogenesis in both non-hematopoietic and hematopoietic malignancies.More recently it has been shown that a small inversion within chromosome2p results in the formation of a fusion gene comprising portions of theechinoderm microtubule-associated protein-like 4 (EML4) gene and theanaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer(NSCLC) cells (Soda M., et al., Nature, 2007, 448, 561-567).

We therefore envision that an ALK inhibitor would either permit durablecures when used as a single therapeutic agent or combined with currentchemotherapy for ALCL, IMT, proliferative disorders, glioblastoma andother possible solid tumors cited herein, or, as a single therapeuticagent, could be used in a maintenance role to prevent recurrence inpatients in need of such a treatment.

Pharmaceutical Methods

The method of the invention comprises administering to a subject in needthereof a therapeutically effective amount of a compound of theinvention.

A “therapeutically effective amount” is that amount effective fordetectable killing or inhibition of the growth or spread of cancercells; the size or number of tumors; or other measure of the level,stage, progression or severity of the cancer. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the disease, theparticular anticancer agent, its mode of administration, combinationtreatment with other therapies, and the like.

The compound, or a composition containing the compound, may beadministered using any amount and any route of administration effectivefor killing or inhibiting the growth of tumors or other forms of cancer.

The anticancer compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of anticancer agent appropriate for the patient to betreated. As is normally the case, the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician using routine reliance upon sound medical judgment.The specific therapeutically effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated; the severity of the disorder; the potency of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the route andschedule of administration; the rate of metabolism and/or excretion ofthe compound; the duration of the treatment; drugs used in combinationor coincident with administration of the compound of this invention; andlike factors well known in the medical arts.

Furthermore, after formulation with an appropriate pharmaceuticallyacceptable carrier in a desired dosage, the compositions of thisinvention can be administered to humans and other animals orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by transdermal patch, powders,ointments, or drops), sublingually, bucally, as an oral or nasal spray,or the like.

The effective systemic dose of the compound will typically be in therange of 0.01 to 500 mg of compound per kg of patient body weight,preferably 0.1 to 125 mg/kg, and in some cases 1 to 25 mg/kg,administered in single or multiple doses. Generally, the compound may beadministered to patients in need of such treatment in a daily dose rangeof about 50 to about 2000 mg per patient. Administration may be once ormultiple times daily, weekly (or at some other multiple-day interval) oron an intermittent schedule. For example, the compound may beadministered one or more times per day on a weekly basis (e.g. everyMonday) indefinitely or for a period of weeks, e.g. 4-10 weeks.Alternatively, it may be administered daily for a period of days (e.g.2-10 days) followed by a period of days (e.g. 1-30 days) withoutadministration of the compound, with that cycle repeated indefinitely orfor a given number of repetitions, e.g. 4-10 cycles. As an example, acompound of the invention may be administered daily for 5 days, thendiscontinued for 9 days, then administered daily for another 5 dayperiod, then discontinued for 9 days, and so on, repeating the cycleindefinitely, or for a total of 4-10 times.

The amount of compound which will be effective in the treatment orprevention of a particular disorder or condition will depend in part onwell known factors affecting drug dosage. In addition, in vitro or invivo assays may optionally be employed to help identify optimal dosageranges. A rough guide to effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.The precise dosage level should be determined by the attending physicianor other health care provider and will depend upon well known factors,including route of administration, and the age, body weight, sex andgeneral health of the individual; the nature, severity and clinicalstage of the disease; the use (or not) of concomitant therapies; and thenature and extent of genetic engineering of cells in the patient.

When administered for the treatment or inhibition of a particulardisease state or disorder, the effective dosage of the compound of thisinvention may vary depending upon the particular compound utilized, themode of administration, the condition, and severity thereof, of thecondition being treated, as well as the various physical factors relatedto the individual being treated. In many cases, satisfactory results maybe obtained when the compound is administered in a daily dosage of fromabout 0.01 mg/kg-500 mg/kg, preferably between 0.1 and 125 mg/kg, andmore preferably between 1 and 25 mg/kg. The projected daily dosages areexpected to vary with route of administration. Thus, parenteral dosingwill often be at levels of roughly 10% to 20% of oral dosing levels.

When the compound of this invention is used as part of a combinationregimen, dosages of each of the components of the combination areadministered during a desired treatment period. The components of thecombination may administered at the same time; either as a unitarydosage form containing both components, or as separate dosage units; thecomponents of the combination can also be administered at differenttimes during a treatment period, or one may be administered as apretreatment for the other.

Regarding the Compounds

Compounds of present invention can exist in free form for treatment, orwhere appropriate, as a pharmaceutically acceptable salt or otherderivative. As used herein, the term “pharmaceutically acceptable salt”refers to those salts which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response andthe like, and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts of amines, carboxylic acids,phosphonates and other types of compounds, are well known in the art.For example, S. M. Berge, et al. describe pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977),incorporated herein by reference. The salts can be prepared in situduring the isolation and purification of the compounds of the invention,or separately by reacting the free base or free acid of a compound ofthe invention with a suitable base or acid, respectively. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

Additionally, as used herein, the term “pharmaceutically acceptableester” refers preferably to esters which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Suitable ester groups include, for example,those derived from pharmaceutically acceptable aliphatic carboxylicacids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioicacids, in which each alkyl or alkenyl moiety advantageously has not morethan 6 carbon atoms. Examples of particular esters include formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.Obviously, esters can be formed with a hydroxyl or carboxylic acid groupof the compound of the invention.

Furthermore, the term “pharmaceutically acceptable prodrugs” as usedherein refers to those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” refers tocompounds that are transformed in vivo to yield the parent compound ofthe above formula, for example by hydrolysis in blood. See, e.g., T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series, and Edward B. Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein byreference.

Compositions

Accordingly, compositions are provided, which comprise any one of thecompounds described herein (or a prodrug, pharmaceutically acceptablesalt or other pharmaceutically acceptable derivative thereof), and oneor more pharmaceutically acceptable carriers or excipients. Thesecompositions optionally further comprise one or more additionaltherapeutic agents. Alternatively, a compound of this invention may beadministered to a patient in need thereof in combination with theadministration of one or more other therapeutic regimens (e.g. Gleevecor other kinase inhibitors, interferon, bone marrow transplant, farnesyltransferase inhibitors, bisphosphonates, thalidomide, cancer vaccines,hormonal therapy, antibodies, radiation, etc). For example, additionaltherapeutic agents for conjoint administration or inclusion in apharmaceutical composition with a compound of this invention may beanother one or more anticancer agents.

As described herein, the compositions of the present invention comprisea compound of the invention together with a pharmaceutically acceptablecarrier, which, as used herein, includes any and all solvents, diluents,or other vehicle, dispersion or suspension aids, surface active agents,isotonic agents, thickening or emulsifying agents, preservatives, solidbinders, lubricants and the like, as suited to the particular dosageform desired. Remington's Pharmaceutical Sciences, Fifteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1975) discloses variouscarriers used in formulating pharmaceutical compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutical composition, its use is contemplatedto be within the scope of this invention. Some examples of materialswhich can serve as pharmaceutically acceptable carriers include, but arenot limited to, sugars such as lactose, glucose and sucrose; starchessuch as corn starch and potato starch; cellulose and its derivativessuch as sodium carboxymethyl cellulose, ethyl cellulose and celluloseacetate; powdered tragacanth; malt; gelatin; talc; excipients such ascocoa butter and suppository waxes; oils such as peanut oil, cottonseedoil; safflower oil; sesame oil; olive oil; corn oil and soybean oil;glycols; such a propylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition.

Formulations

This invention also encompasses a class of compositions comprising theactive compounds of this invention in association with one or morepharmaceutically-acceptable carriers and/or diluents and/or adjuvants(collectively referred to herein as “carrier” materials) and, ifdesired, other active ingredients. The active compounds of the presentinvention may be administered by any suitable route, preferably in theform of a pharmaceutical composition adapted to such a route, and in adose effective for the treatment intended. The compounds andcompositions of the present invention may, for example, be administeredorally, mucosally, topically, rectally, pulmonarily such as byinhalation spray, or parentally including intravascularly,intravenously, intraperitoneally, subcutaneously, intramuscularly,intrasternally and infusion techniques, in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers, adjuvants,and vehicles.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient.

Examples of such dosage units are tablets or capsules. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more commonly from about 5 to 200mg. A suitable daily dose for a human or other mammal may vary dependingon the condition of the patient and other factors, but, once again, canbe determined using routine methods.

The amount of compounds which are administered and the dosage regimenfor treating a disease condition with the compounds and/or compositionsof this invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. Atypical daily dose is in the range of 0.01 to 500 mg of compound per kgbody weight, preferably between 0.1 and 125 mg/kg body weight and insome cases between 1 and 25 mg/kg body weight. As mentioned previously,the daily dose can be given in one administration or may be dividedbetween 2, 3, 4 or more administrations.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants, excipients or carriersappropriate to the indicated route of administration. If administeredper os, the compounds may be admixed with lactose, sucrose, starchpowder, cellulose esters of alkanoic acids, cellulose alkyl esters,talc, stearic acid, magnesium stearate, magnesium oxide, sodium andcalcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andthen tableted or encapsulated for convenient administration. Suchcapsules or tablets may contain a controlled-release formulation as maybe provided in a dispersion of active compound in hydroxypropyl methylcellulose.

In the case of skin conditions, it may be preferable to apply a topicalpreparation of compounds of this invention to the affected area two tofour times a day.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at Least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include dimethylsulfoxide and relatedanalogs.

The compounds of this invention can also be administered by atransdermal device. Preferably transdermal administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered—continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner.

While the phase may comprise merely an emulsifier, it may comprise amixture of at least one emulsifier with a fat or an oil or with both afat and an oil. Preferably, a hydrophilic emulsifier is includedtogether with a lipophilic emulsifier which acts as a stabilizer. It isalso preferred to include both an oil and a fat. Together, theemulsifier(s) with or without stabilizer(s) make-up the so-calledemulsifying wax, and the wax together with the oil and fat make up theso-called emulsifying ointment base which forms the oily dispersed phaseof the cream formulations. Emulsifiers and emulsion stabilizers suitablefor use in the formulation of the present invention include Tween 60,Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate,sodium lauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired.

Alternatively, high melting point lipids such as white soft paraffinand/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients.

The active ingredients are preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% and particularlyabout 1.5% w/w.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers.

Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art. The active ingredient may also be administeredby injection as a composition with suitable carriers including saline,dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolventsolubilization (i.e. propylene glycol) or micellar solubilization (i.e.Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Pharmaceutical compositions of this invention comprise a compound of theformulas described herein or a pharmaceutically acceptable salt thereof;an additional agent selected from a kinase inhibitory agent (smallmolecule, polypeptide, antibody, etc.), an immunosuppressant, ananticancer agent, an anti-viral agent, antiinflammatory agent,antifungal agent, antibiotic, or an anti-vascular hyperproliferationcompound; and any pharmaceutically acceptable carrier, adjuvant orvehicle.

Alternate compositions of this invention comprise a compound of theformulae described herein or a pharmaceutically acceptable salt thereof;and a pharmaceutically acceptable carrier, adjuvant or vehicle. Suchcompositions may optionally comprise one or more additional therapeuticagents, including, for example, kinase inhibitory agents (smallmolecule, polypeptide, antibody, etc.), immunosuppressants, anti-canceragents, anti-viral agents, antiinflammatory agents, antifungal agents,antibiotics, or anti-vascular hyperproliferation compounds.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a patient, together witha compound of this invention, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, selfemulsifying drug delivery systems (SEDDS) such asd-atocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as u-, P-, and y-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2 and 3-hydroxypropyl-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.

If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The pharmaceutical compositions of this invention may compriseformulations utilizing liposome or microencapsulation techniques,various examples of which are known in the art.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents, examplesof which are also well known in the art.

Combinations

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more other compounds of the invention or with one or more otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administered at the sametime or sequentially at different times, or the therapeutic agents canbe given as a single composition.

The phrase “combination therapy”, in referring to the use of a compoundof this invention together with another pharmaceutical agent, means thecoadministration of each agent in a substantially simultaneous manner aswell as the administration of each agent in a sequential manner, ineither case, in a regimen that will provide beneficial effects of thedrug combination. Coadministration includes inter alia the simultaneousdelivery, e.g., in a single tablet, capsule, injection or other dosageform having a fixed ratio of these active agents, as well as thesimultaneous delivery in multiple, separate dosage forms for each agentrespectively.

Thus, the administration of compounds of the present invention may be inconjunction with additional therapies known to those skilled in the artin the prevention or treatment of cancer, such as radiation therapy orcytostatic agents, cytotoxic agents, other anti-cancer agents and otherdrugs to ameliorate symptoms of the cancer or side effects of any of thedrugs.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof this invention may also be administered sequentially with otheranticancer or cytotoxic agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of this invention may be administered priorto, simultaneously with, or after administration of the other anticanceror cytotoxic agent.

Currently, standard treatment of primary tumors consists of surgicalexcision, when appropriate, followed by either radiation orchemotherapy, and typically administered intravenously (IV). The typicalchemotherapy regime consists of either DNA alkylating agents, DNAintercalating agents, CDK inhibitors, or microtubule poisons. Thechemotherapy doses used are just below the maximal tolerated dose andtherefore dose limiting toxicities typically include, nausea, vomiting,diarrhea, hair loss, neutropenia and the like.

There are large numbers of antineoplastic agents available in commercialuse, in clinical evaluation and in pre-clinical development, which wouldbe selected for treatment of cancer by combination drug chemotherapy.And there are several major categories of such antineoplastic agents,namely, antibiotic-type agents, alkylating agents, antimetaboliteagents, hormonal agents, immunological agents, interferon-type agentsand a category of miscellaneous agents.

A first family of antineoplastic agents which may be used in combinationwith compounds of the present invention includesantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom but not limited to the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,CibaGeigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co.

EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil,N-(21-furanidyl) fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC788, thioguanine, tiazofurin, Erbamont trimetrexate, tyrosine kinaseinhibitors, Taiho UFT and uricytin.

A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine,anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane,Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558,Sanofi CY-233, cyplatate, Degussa D 384, Sumimoto DACHP(Myr)₂,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unimed G M, ChinoinGYKI-17230, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide,mitolactolf Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine,Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone,tetraplatin and trimelamol.

A third family of antineoplastic agents which may be used in combinationwith compounds of the present invention consists of antibiotic-typeantineoplastic agents. Suitable antibiotic-type antineoplastic agentsmay be selected from but not limited to the group consisting of Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN II, Ajinomoto AN3, Nippon Sodaanisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-MyersBL-6859, Bristol-Myers BMY-25067, Bristol-Myers BNY-25551, Bristol-MyersBNY-26605 IBristolMyers BNY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko, DC89-Al, Kyowa Hakko DC92-B, ditrisarubicinB, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb,Erbamont FCE21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin,mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, NipponKayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents, including tubulininteracting agents, topoisomerase II inhibitors, topoisomerase Iinhibitors and hormonal agents, selected from but not limited to thegroup consisting of (xcarotene, (X-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5. antineoplaston AS2-1F HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluoron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,BristoMyers BNY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502,Wellcome BW-773, caracemide, carmethizole hydrochloride, Ajinomoto CDAF,chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-LambertCI-921, WarnerLambert CI-937, Warner-Lambert CI-941, Warner-LambertCI958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711,Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B.cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine,datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone,dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, DaiichiSeiyaku DN-9693, docetaxel elliprabin, elliptinium acetate, TsumuraEPMTC, the epothilones, ergotamine, etoposide, etretinate, fenretinide,Fujisawa FR-57704t gallium nitrate, genkwadaphnin, Chugai GLA-43, GlaxoGR-63178, grifolan NMF5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine,isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, KurehaChemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin,lonidamine, Lundbeck LU 1121 Lilly LY-186641, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanlnederivatives, methylanilinoacridine, Molecular Genetics MGI136,minactivin, mitonafide, mitoquidone mopidamol, motretinide, ZenyakuKogyo MST-16, N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, WarnerLambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as acemannan,aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine,amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide,anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002(Novelos), bexarotene, bicalutamide, broxuridine, capecitabine,celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate,DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin,dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol,doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine,fluorouracil, HIT diclofenac, interferon alfa, daunorubicin,doxorubicin, tretinoin, edelfosine, edrecolomab eflornithine, emitefur,epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind,fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane,fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin,gimeracil/oteracil/tegafur combination, glycopine, goserelin,heptaplatin, human chorionic gonadotropin, human fetal alphafetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa,interferon alfa, natural, interferon alfa-2, interferon alfa-2a,interferon alfa-2b, interferon alfa-NI, interferon alfa-n3, interferonalfaconl, interferon alpha, natural, interferon beta, interferonbeta-1a, interferon beta-1b, interferon gamma, natural interferongamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane,irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide,lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon,leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone,mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone+pentazocine,nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesisstimulating protein, NSC 631570 octreotide, oprelvekin, osaterone,oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferonalfa-2b, pentosan polysulfate sodium, pentostatin, picibanil,pirarubicin, rabbit antithymocyte polyclonal antibody, polyethyleneglycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed,rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab,romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofuran,sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin,tazarotene, tegafur, temoporfin, temozolomide, teniposide,tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa,topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan,tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factoralpha, natural, ubenimex, bladder cancer vaccine, Maruyama. vaccine,melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine,VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941(Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide,diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,etanidazole, fenretinidel filgrastim SDO1 (Amgen), fulvestrant,galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypicCEA MAb (Trilex), LYM iodine 131 MAb (Techniclone), polymorphicepithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril,mitumomab, motexafin, gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN)y SU6668 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine,thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine(Biomira), melanoma vaccine (New York University), melanoma vaccine(Sloan Kettering Institute), melanoma oncolysate vaccine (New YorkMedical College), viral melanoma cell lysates vaccine (Royal NewcastleHospital), or valspodar.

In another embodiment of interest in this invention, a compound of thisinvention can be used in combination with other bcr-abl inhibitors suchas for example Nilotinib, Dasatinib, Bosutinib and INNO-406. Theseparticular combinations with other bcr-abl inhibitors can be used forthe treatment of cancers mediated by dysregulation of Bcr-Abl or mutantthereof such as for example chronic myeloid leukemia (CML) or acutemyeloid leukemia (AML).

Again, we contemplate that compounds of this invention in combinationtherapies, will be useful against leukemias and other cancers, includingthose which are resistant in whole or part to other anticancer agents,specifically including Gleevec and other kinase inhibitors, andspecifically including leukemias involving one or more mutations inBCR/Abl, within or outside the kinase domain, including but not limitedto Y253H, E255K, T315I, F311L and those noted in any of the foregoingpublications. See also Azam et al. and references cited therein forexamples of such mutations in BCR/Abl, including, among others,mutations in the drug binding cleft, the phosphate binding P loop, theactivation loop, the conserved VAVK of the kinase beta-3 sheet, thecatalytic alpha-1 helix of the small N lobe, the long alpha-3 helixwithin the large C lobe, and the region within the C lobe downstream ofthe activation loop. See also Shah et al., J. Clin. Invest 117(9),2562-2569 (2007); Stagno et al. Leukemia Research, 32(4), 665-667(2007); Khorasha et al., blood 112(8), 3500-3507 (2008) forrepresentative examples of such mutations in Bcr/Abl which correlatewith dasatinib resistance.

Treatment Kits

In other embodiments, the present invention relates to a kit forconveniently and effectively carrying out the methods in accordance withthe present invention. In general, the pharmaceutical pack or kitcomprises one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. Suchkits are especially suited for the delivery of solid oral forms such astablets or capsules. Such a kit preferably includes a number of unitdosages, and may also include a card having the dosages oriented in theorder of their intended use. If desired, a memory aid can be provided,for example in the form of numbers, letters, or other markings or with acalendar insert, designating the days in the treatment schedule in whichthe dosages can be administered. Optionally associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticalproducts, which notice reflects approval by the agency of manufacture,use or sale for human administration.

The following representative examples contain important additionalinformation, exemplification and guidance which can be adapted to thepractice of this invention in its various embodiments and theequivalents thereof. These examples are intended to help illustrate theinvention, and are not intended to, nor should they be construed to,limit its scope. Indeed, various modifications of the invention, andmany further embodiments thereof, in addition to those shown anddescribed herein, will become apparent to those skilled in the art uponreview of this document, including the examples which follow and thereferences to the scientific and patent literature cited herein. Thecontents of those cited references are incorporated herein by referenceto help illustrate the state of the art. In addition, for purposes ofthis invention, the chemical elements are identified in accordance withthe Periodic Table of the Elements, CAS version, Handbook of Chemistryand Physics, 75^(th) Ed., inside cover. Additionally, general principlesof organic chemistry, as well as specific functional moieties andreactivity, are described in “Organic Chemistry”, Thomas Sorrell,University Science Books, Sausalito: 1999, and “Organic Chemistry”,Morrison & Boyd (3d Ed), the entire contents of both of which areincorporated herein by reference.

Example 13-[1-(benzyloxy)-1H-pyrrolo[3,2-b]pyridin-6-yl]-N,N-dimethylbenzamide

Diethyl (5-bromo-3-nitropyridin-2-yl)propanedioate: In a 3-necked flask,NaH (60%, 2.2 g, 54.8 mmol, 1.3 eq) was washed with hexanes under N₂once. To the flask, 40 ml of dry N,N-dimethylformamide (DMF) was addedand the reaction mixture was cooled to 0° C. To this suspension wasadded diethylmalonate (8.77 g, 54.8 mmol, 1.3 eq) dropwise. The mixturewas stirred at 0° C. for 15 min and at room temperature for 15 min.5-bromo-2-chloro-3-nitropyridine (9.6 g, 40.4 mmol, 1.0 eq) in 20 ml ofDMF was slowly added to the reaction mixture. The reaction was heated to60° C. for 1 hour and then at 100° C. for 2 hours. The reaction mixturewas allowed to cool down to room temperature, water was added, and thesolution was neutralized with acetic acid and evaporated. The mixturewas chromatographed (EtOAc/Hexanes 1:10) to give a yellow oil, 12.5 g,in 85% yield.

5-bromo-2-methyl-3-nitropyridine: diethyl(5-bromo-3-nitropyridin-2-yl)propanedioate (6.8 g, 18.8 mmol) wasrefluxed in 290 ml of 6M HCl overnight. The reaction mixture was allowedto cool down to room temperature, and the mixture was neutralized withNaOH in an ice bath to pH 10. The solution was extracted withdichloromethane (DCM), dried, and evaporated to a yellow solid, 3.88 g,in 95% yield.

(E)-2-(5-bromo-3-nitropyridin-2-yl)-N,N-dimethylethenamine: A solutionof 5-bromo-2-methyl-3-nitropyridine (3.0 g, 13.8 mmol) andN—N-dimethylformamide-dimethylacetal (DMF-DMA) in 45 ml of DMF washeated at 90° C. for 4 hours, and cooled to room temperature. Thesolvent was evaporated and the residue dissolved in dichloromethane(DCM), which was washed with saturated NaHCO₃ and brine, andchromatographed (EtOAc/Hexanes 1:10) to give a red solid, 2.86 g, in 76%yield.

6-bromo-1H-pyrrolo[3,2-b]pyridin-1-ol: A suspension of(E)-2-(5-bromo-3-nitropyridin-2-yl)-N,N-dimethylethenamine (2.86 g, 10.5mmol) and SnCl₂.2H₂O (12 g, 100 mmol) in 35 ml of ethyl acetate wasstirred at room temperature overnight. 100 ml of ethyl acetate was addedand the organic layer was washed with saturated NH₄Cl and then withbrine. After evaporation, the crude product was chromatographed(MeOH/DCM 1:20) to give a yellow solid, 1.6 g, in 77% yield.

1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine:6-bromo-1H-pyrrolo[3,2-b]pyridin-1-ol: (2.7 g, 13.7 mmol, 1.0 eq),benzyl bromide (3.57 g, 20.9 mmol, 1.5 eq), and KI (2.31 g) weresuspended in 29 ml of 2M K₂CO₃ and 55 ml of N,N-dimethylformamide (DMF).The reaction was stirred at 50° C. for 1 hour and 100° C. for 1.5 hours.The reaction mixture was allowed to cool down to room temperature, thesolvent was evaporated, and the mixture was chromatographed (MeOH/DCM1:50) to give a light yellow oil, 1.1 g, in 28% yield.

3-[1-(benzyloxy)-1H-pyrrolo[3,2-b]pyridin-6-yl]-N,N-dimethylbenzamide: Asolution of 1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine (60 mg, 0.21mmol, 1.0 eq), Pd(PPh₃)₄ (13 mg), 2.0 M K₂CO₃ (1.0 ml), DMF (1.2 ml),and [3-(dimethylcarbamoyl)phenyl]boronic acid (1.5 eq, 0.315 mmol) werereacted in microwave (110° C.) for 20 minutes. The upper layer wasremoved with a pipette and filtered, and purified with preparation HPLCto give the desired product.

Example 26-(1-benzothiophen-3-yl)-1-(benzyloxy)-1H-pyrrolo[3,2-b]pyridine

The entitled compound was prepared from1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine and1-benzothiophen-3-ylboronic acid according to the procedure described inExample 1.

Example 31-(benzyloxy)-6-(1-methyl-1H-indol-5-yl)-1H-pyrrolo[3,2-b]pyridine

The entitled compound was prepared from1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine and(1-methyl-1H-indol-5-yl)boronic acid according to the proceduredescribed in Example 1.

Example 4(3-{1-[1-(2,6-dichloro-3-fluorophenyl]ethoxyl-1H-pyrrolo[3,2-b]pyridin-6-yl}phenyl)(morpholin-4-yl)methanone

1-(2,6-dichloro-3-fluorophenyl)ethanol: To 12 ml of methanol at 0° C.was added 1.55 g (41.1 mmol, 1.7 eq) of NaBH₄, followed by a solution of1-(2,6-dichloro-3-fluorophenyl)ethanone (5.0 g, 24.1 mmol, 1.0 eq) in 10ml of methanol. The reaction was warmed to room temperature (r.t.) andstirred for 2 hours. A 1.0M HCl solution was added, and the solution wasextracted with dichloromethane (DCM), dried, and evaporated to a whitesolid, 5.6 g, in 111% crude yield. The product was used for nextreaction without further purification.

1-(2,6-dichloro-3-fluorophenyl)ethyl methanesulfonate:1-(2,6-dichloro-3-fluorophenyl)ethanol (5.2 g, 24.9 mmol),methanesulfonyl chloride (6.3 g, 55 mmol, 2.2 eq), and triethylamine(6.1 g) were stirred in 50 ml of DCM and 12 ml of DMF at roomtemperature overnight. Water and DCM were added, and the layers wereseparated. The aqueous layer was extracted with DCM. The combinedorganic layers were dried, evaporated and chromatographed (EtOAc/Hexanes1:10) to give an oil, 5.11 g, in 71% yield.

6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine:A solution of 1-(2,6-dichloro-3-fluorophenyl)ethyl methanesulfonate(4.39 g, 15.3 mmol, 1.0 eq), 6-bromo-1H-pyrrolo[3,2-b]pyridin-1-ol(prepared as in example 1: 3.92 g, 20.0 mmol, 1.3 eq) and K₂CO₃ (6.34 g,45.9 mmol, 3.0 eq) in 90 ml of N,N-dimethylformamide (DMF) was stirredat room temperature overnight. The solid was filtered out and thesolvent evaporated. The residue was dissolved in DCM, and the solutionwas washed with water and brine, dried, evaporated and chromatographed(MeOH/DCM 1:20) to give a light yellow oil, 4.63 g, in 78% yield.

(3-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}phenyl)(morpholin-4-yl)methanone:To a solution of6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine(75 mg, 0.195 mmol, 1.0 eq) in DMF (1.2 mL), was added Pd(PPh₃)₄ (15mg), 2.0 M K₂CO₃ (1.0 mL), and [3-(morpholin-4-ylcarbonyl)phenyl]boronicacid (1.8 eq, 0.351 mmol). The reaction mixture was microwaved at 90° C.for 30 minutes. The upper layer was removed with a pipette, filtered,and purified with preparation HPLC to give the product.

Example 53-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}-N-[2-(dimethylamino)ethyl]benzamide

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand (3-{[2-(dimethylamino)ethyl]carbamoyl}phenyl)boronic acid accordingto the procedure described in example 4.

Example 63-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}-N,N-dimethylbenzamide

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand [3-(dimethylcarbamoyl)phenyl]boronic acid according to the proceduredescribed in example 4.

Example 73-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}benzamide

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand (3-carbamoylphenyl)boronic acid according to the procedure describedin example 4.

Example 8(3-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}phenyl)Methanol

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand [3-(hydroxymethyl)phenyl]boronic acid according to the proceduredescribed in example 4.

Example 9N-cyclopropyl-4-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}benzamide

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand [4-(cyclopropylcarbamoyl)phenyl]boronic acid according to theprocedure described in example 4.

Example 103-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}aniline

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand (3-aminophenyl)boronic acid according to the procedure described inexample 4.

Example 114-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}-N-(2-hydroxyethyl)benzenesulfonamide

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand {4-[(2-hydroxyethyl)sulfamoyl]phenyl}boronic acid according to theprocedure described in example 4.

Example 125-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}quinoline

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand quinolin-5-ylboronic acid according to the procedure described inexample 4.

Example 131-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-(1-methyl-1H-indol-5-yl)-1H-pyrrolo[3,2-b]pyridine

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand (1-methyl-1H-indol-5-yl)boronic acid according to the proceduredescribed in example 4.

Example 141-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-(1H-indol-6-yl)-1H-pyrrolo[3,2-b]pyridine

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand 1H-indol-6-ylboronic acid according to the procedure described inexample 4.

Example 151-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridine

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylateaccording to the procedure described in example 4. The resultingcompound (BOC protected compound) was dissolved in methanol and wastreated with HCl (4.0M solution in dioxane,) at room temperature for 30min. Solvents were evaporated and the residue was dissolved in DCM andtreated with Na₂CO₃/NaHCO₃ and drops of water. The solution was thenpurified to give the entitled compound.

tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate: tert-Butyl4-hydroxypiperidine-1-carboxylate (60.0 g, 0.3 mol, 1.0 eq),methanesulfonyl chloride (37.6 g, 0.33 mol, 1.1 eq), and triethylamine(36.2 g, 0.36 mol, 1.2 eq) in 600 ml of dichloromethane (DCM) wasstirred at room temperature overnight. Water (300 ml) was added and thelayers were separated. The aqueous layer was extracted with DCM once.The combined organics were washed with brine, dried, and evaporated to ayellowish solid, 80.5 g, in 97% yield.

tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate: A mixtureof tert-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate: (75.5 g,0.271 mol), 4-iodopyrazole (52.5 g, 0.271 mol), and K₂CO₃ (11.3 g, 0.8mol) in 1.5 L of N,N-dimethylformamide (DMF) was stirred at 100° C.overnight. After cooled to r.t., the solvent was evaporated. The residuewas dissolved in DCM, filtered, and washed with water and brine. Theorganic layer was dried and evaporated to an oil. The crude product waspurified by chromatography (MeOH/DCM 1:40) and (EtOH/MeOH 10%-20%) togive 52g of the product as a white solid after standing, in 51% yield.

tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate:Bis(pinacolato)diboron (14.2 g, 55.9 mmol, 1.4 eq) and potassium acetate(15.8 g, 161 mmol, 4.0 eq) were added to a solution of tert-butyl4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate (15.0 g, 39.8 mmol,1.0 eq) in dimethylsulfoxide (DMSO) (173 nil) sequentially undernitrogen. Pd(PPh₃)₄ (3.98 g) was then added. The reaction was heated at80° C. for 2 hours. The mixture was cooled to room temperature (r.t.),filtered through celite and washed with ethyl acetate. The filtrate waswashed with brine twice, dried, and chromatographed (5%-30% of ethylacetate in hexanes) to give a yellowish solid, 12.5 g, in 83% yield.

Example 166-(1-benzyl-1H-pyrazol-4-yl)-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand (1-benzyl-1H-pyrazol-4-yl)boronic acid according to the proceduredescribed in example 4.

Example 17N-(3-{1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridin-6-yl}phenyl)acetamide

The entitled compound was prepared from6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridineand [3-(acetylamino)phenyl]boronic acid according to the proceduredescribed in example 4.

Example 186-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1-{[2-(trifluoromethyl)benzyl]oxy}-1H-pyrrolo[3,2-b]pyridine

tert-butyl4-[4-(6-methyl-5-nitropyridin-3-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate:5-bromo-2-methyl-3-nitropyridine (4.6 g, 21 mmol, 1.0 eq) and 424 mg ofPd(PPh₃)₄ were stirred in dimethoxyethane (DME) (17 ml) at r.t. for 20min, and then tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(prepared as in Example 15) in isopropanol (21 ml) was added followed bya 2.0 M solution of K₂CO₃ (15 ml). The reaction mixture was stirred at85° C. overnight, the mixture was cooled to room temperature andevaporated. The mixture was purified with ISCO (MeOH/DCM 1:20) to ayellow solid, 7.75 g, in 95% yield.

tert-butyl4-(4-{6-[(E)-2-(dimethylamino)ethenyl]-5-nitropyridin-3-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate:A solution of tert-butyl4-[4-(6-methyl-5-nitropyridin-3-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(7.7 g) and N—N-dimethylformamide-dimethylacetal (DMF-DMA) (10g) in 50ml of DMF was heated at 90° C. overnight and cooled to room temperature.The solvent was evaporated and the residue dissolved in DCM, which waswashed with sat. NaHCO₃ and brine, and evaporated to give a red solid,9.0 g of crude product.

tert-butyl4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate:tert-butyl4-(4-{6-[(E)-2-(dimethylamino)ethenyl]-5-nitropyridin-3-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate(366 mg, 0.81 mmol) and SnCl₂.2H₂O (966 mg, 4.26 mmol, 5.0 eq) in 3 mlof EtOAc were stirred at r.t. for 2 hours. EtOAc and water were addedand layers were separated. The aqueous layer was extracted with EtOAc,washed with sat. NH₄Cl and brine. After evaporation, the crude productwas chromatographed (Mesh/DCM 1:20) to give a yellow solid, 170 mg, in54% yield.

6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1-{[2-(trifluoromethyl)benzyl]oxy}-1H-pyrrolo[3,2-b]pyridine:tert-butyl4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(30 mg, 0.078 mmol, 1.0 eq), 1-(bromomethyl)-2-(trifluoromethyl)benzene(0.066 mmol), and K₂CO₃ (30 mg) in 1.5 ml of DMF were shaken at r.t. for30 min and then filtered and evaporated. The resulting crude product wasdissolved in 1.5 ml of methanol and 0.5 ml of 4.0 M HCl/dioxane wasdropped in. The reaction was shaken at room temperature for 0.5-1 h. Thesolvent was evaporated and the residue was dissolved in 2 ml of DCM. Tothis solution were added 20 mg of NaHCO₃, 10 mg of Na₂CO₃, and drops ofwater. After stirred for 10 min, the organic solution was separated andpurified with preparation HPLC to give the final product.

Example 191-{[5-fluoro-2-(trifluoromethyl)benzyl]oxy}-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridine

The entitled compound is prepared from tert-butyl4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylateand 2-(bromomethyl)-4-fluoro-1-(trifluoromethyl)benzene as described inthe last 2 steps of Example 18.

Example 206-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1-{[4-(trifluoromethoxy)benzyl]oxy}-1H-pyrrolo[3,2-b]pyridine

The entitled compound is prepared from tert-butyl4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylateand 1-(bromomethyl)-4-(trifluoromethoxy)benzene as described in the last2 steps of Example 18.

Example 216-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1-(pyrimidin-2-yloxy)-1H-pyrrolo[3,2-b]pyridine

The entitled compound is prepared from tert-butyl4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylateand 2-bromo-pyrimidine as described in the last 2 steps of Example 18.

Example 221-{[3-(4-fluorophenoxy)benzyl]oxy}-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridine

The entitled compound is prepared from tert-butyl4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylateand 1-(bromomethyl)-3-(4-fluorophenoxy)benzene as described in the last2 steps of Example 18.

Example 236-(1-methyl-1H-indol-5-yl)-1-phenoxy-1H-pyrrolo[3,2-b]pyridine

6-bromo-1-phenoxy-4H-pyrrolo[3,2-b]pyridine:6-bromo-1H-pyrrolo[3,2-b]pyridin-1-ol (prepared as in Example 1: 200 mg,1.0 mmol, 1.0 eq), fluorobenzene (485 mg, 5.0 mmol, 5.0 eq), and K₂CO₃(690 mg, 5.0 mmol, 5.0 eq) in 2 ml of DMF were microwaved (160° C.) for30 min. The reaction mixture was allowed to cool to room temperature,the solvent was evaporated, and the mixture was chromatographed(MeOH/DCM 1:20) to give a light yellow solid, 110 mg, in 50% yield.

6-(1-methyl-1H-indol-5-yl)-1-phenoxy-1H-pyrrolo[3,2-b]pyridine:6-bromo-1-phenoxy-1H-pyrrolo[3,2-b]pyridine (56 mg, 0.205 mmol, 1.0 eq),Pd(PPh₃)₄ (13 mg), 2.0 M K₂CO₃ (1.0 ml), DMF (1.2 ml), and(1-methyl-1H-indol-5-yl)boronic acid (1.5 eq, 0.315 mmol) were refluxedunder N₂ overnight. The crude products were purified with preparationHPLC to give the product in 50%.

Example 24 6-(1-benzofuran-5-yl)-1-phenoxy-1H-pyrrolo[3,2-b]pyridine

The entitled compound was prepared from6-bromo-1-phenoxy-1H-pyrrolo[3,2-b]pyridine and 1-benzofuran-5-ylboronicacid in a 25% yield according to the procedure described in example 23.

Example 25N-benzyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine

6-bromo-1H-pyrrolo[3,2-b]pyridin-1-amine: To a solution of6-Bromo-1H-pyrrolo[3,2-b]pyridine (1.9 g, 10 mmol) in 20 mL of DMF at 0°C. was added NaH (60% in oil, 0.49 g, 12 mmol) in three portions. Themixture was stirred at room temperature for 30 min. A solution of NH₂Clin Et₂O (prepared according to the procedure described in J. Org. Chem.2004, 1371: ˜0.15 M, 80 mL) was added at −20° C. The mixture was warmedup to room temperature for 15 min and was poured into a saturatedsolution of thiosulfate and ammonium chloride, and extracted with ethylacetate. The organic layer was concentrated and the residue washed withsmall amount of ethyl acetate to give pink solid (1.3 g, 62% yield)

6-bromo-N-[(E)-phenylmethylidene]-1H-pyrrolo[3,2-b]pyridin-1-amine: Amixture of 6-bromo-1H-pyrrolo[3,2-b]pyridin-1-amine (200 mg, 0.95 mmol)and benzaldehyde (120 mg, 1.2 eq) was heated to 60° C. for 10 min.Heptanes (2.0 ml) was added and the mixture was heated to reflux for 10min. The product was purified by column chromatography(heptane:EtOAc=1:1) to yield a grey solid (130 mg, yield 46%).

N-benzyl-6-bromo-M-pyrrolo[3,2-b]pyridin-1-amine: A mixture of6-bromo-N-[(E)-phenylmethylidene]-1H-pyrrolo[3,2-b]pyridin-1-amine (400mg, 1.34 mmol) in THF (10 mL) was treated with excess amount of LiAlH₄at room temperature. The mixture was stirred at room temperature for 20min and diluted with aq. NH₄Cl, extracted with ethyl acetate. Theproduct was purified by column chromatography (heptane:EtOAc=1:1). Theentitled intermediate was isolated as a white solid (230 mg, yield 57%).

tert-butyl4-{4-[1-(benzylamino)-1H-pyrrolo[3,2-b]pyridin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate:This intermediate was prepared using Suzuki coupling reaction ofN-benzyl-6-bromo-1H-pyrrolo[3,2-b]pyridine-1-amine and tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylateas described in example 1.

N-benzyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine:Removal of the BOC protecting group was achieved using HCl/dioxane asdescribed in Example 18.

Alternative Synthesis:

tert-butyl4-[4-(1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate:To a solution of tert-butyl4-(4-{6-[(E)-2-(dimethylamino)ethenyl]-5-nitropyridin-3-yl}-1H-pyrazol-1-yl)piperidine-1-carboxylate(prepared in example 18: 4.0 g, 9.05 mmol) in MeOH (50 mL) was addedPd—C (10%, wet, 2.0 g) and the reaction mixture was hydrogenated under ahydrogen balloon at room temperature for 2 h. The catalyst was filteredoff and solvent was evaporated. The residue was washed with ethylacetate to give a solid (3.1 g, yield 93%).

tert-butyl4-[4-(1-amino-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate:To a solution of tert-butyl4-[4-(1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate:(0.73 g, 2.0 mmol) in 4.0 mL of DMF at −20° C. was added NaH (60% inoil, 96 mg, 2.4 mmol) in one portion. After 15 min, the mixture wasstirred at room temperature for 30 min. A solution of NH₂Cl in Et₂O(prepared according to the procedure described in J. Org. Chem. 2004,1371: ˜0.15 M, 16 ml) was added. The mixture was poured into a saturatedsolution of thiosulfate and ammonium chloride, and extracted with ethylacetate. The organic layer was concentrated and the product was purifiedby column chromatography (EtOAc:MeOH=100:5). The entitled intermediatewas isolated as a light brown solid (350 mg, 45% yield) (startingmaterial (220 mg) was also recovered).

tert-butyl4-[4-(1-{[(E)-phenylmethylidene]amino}-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate:A mixture of tert-butyl4-[4-(1-amino-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(30 mg, 0.078 mmol) and benzaldehyde (2.0 mL, excess) was heated to 60°C. for 10 min. Heptanes (4.0 ml) was added and the mixture was heated toreflux for 10 min. The product was purified by column chromatography(EtOAc:MeOH=100:5) and the entitled intermediate was isolated as a whitesolid (30 mg, 81% yield).

tert-butyl4-{4-[1-(benzylamino)-1H-pyrrolo[3,2-b]pyridin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate:A mixture of tert-butyl4-[4-(1-{[(E)-phenylmethylidene]amino}-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(200 mg, 0.43 mmol) in MeOH (10 mL) was treated with excess amount ofNaBH₄ under reflux. HPLC check indicates disappearance of the startingmaterial. The mixture was diluted with aqueous NaHCO₃, and extractedwith ethylacetate. The product was purified by column chromatography(EtOAc:MeOH=100:5) and the entitled intermediate was isolated as a whitesolid (180 mg, yield 90%).

N-benzyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine:A solution of tert-butyl4-{4-[1-(benzylamino)-1H-pyrrolo[3,2-b]pyridin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate(25 mg, 0.053 mmol) in MeOH (0.3 mL) was treated with HCl (4.0M solutionin dioxane, 1.5 mL) at room temperature for 30 min. Solvents wereevaporated and the residue was diluted with aq. NaHCO₃, extracted withethyl acetate. The organic layer was dried, filtered and evaporated togive a white solid (10 mg, yield 51%).

Example 26N-benzyl-N-methyl-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine

To a solution of tert-butyl4-{4-[1-(benzylamino)-1H-pyrrolo[3,2-b]pyridin-6-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate(prepared in example 25: 125 mg, 0.26 mmol) in 3.0 mL of DMF at 0° C.was added NaH (60% in oil, 31 mg, 0.78 mmol) in one portion. After 15min, the mixture was treated with methyl iodide. HPLC check showsdisappearance of starting material. Solvent was removed and the residuedissolved in ethyl acetate, washed with aqueous NaHCO₃. The organicsolution was dried, evaporated and then the residue was treated withmethanol (0.5 mL) and HCl (4.0M in dioxane, 2.0 mL) at room temperaturefor 30 min. The solvent was removed and the residue was purified bypreparative HPLC to give product as a white solid (4.1 mg, yield 4%).

Example 27N-(2,6-dichloro-3-fluorobenzyl)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine

(2,6-dichloro-3-fluorophenyl)methanol: A solution of3-fluoro-2,6-dichorobenzoic acid (20 g, 0.10 mol) was treated with SOCl₂(25 mL) under reflux for 10 min. Excess SOCl₂ was removed byevaporation. The residue was dissolved in tetrahydrofuran (THF) (150 mL)and treated with diisobutylaluminium hydride (DIBAL: 1.0 M solution intoluene, 150 mL). The mixture was stirred at room temperature for 1 hand then diluted slowly with aqueous NaHCO₃. The mixture was extractedwith ethyl acetate. The organic layer was dried, evaporated and theresidue was washed with a small amount of DCM to afford a white solid(14g, yield 72%).

2,6-dichloro-3-fluorobenzaldehyde: To a solution of(2,6-dichloro-3-fluorophenyl)methanol (9.0 g, 46 mmol) indichloromethane (200 mL) was added molecular sieves (4A, powder, 40g)and pyridinium dichromate (PDC: 45g, 120 mmol). The mixture was stirredat room temperature for 2 h and diluted with Et₂O (200 mL). The mixturewas filtered through Celite and the solvent was removed in vacuum. Theresidue was washed with a small amount of dichloromethane to give awhite solid (4.6 g, yield 52%).

tert-butyl4-[4-(1-{[(E)-(2,6-dichloro-3-fluorophenyl)methylidene]amino}-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate:A mixture of tert-butyl4-[4-(1-amino-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(100 mg, 0.26 mmol) and 2,6-dichloro-3-fluorobenzaldehyde (50 mg, 0.26mmol) in heptane (2.0 mL) was heated in a sealed tube at 120° C. for 15min. The product was purified by column chromatography (ethyl acetate)to give the desired intermediate as an off-white solid (126 mg, yield87%).

N-[(E)-(2,6-dichloro-3-fluorophenyl)methylidene]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine:A solution of tert-butyl4-[4-(1-{[(E)-(2,6-dichloro-3-fluorophenyl)methylidene]amino}-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(15 mg, 0.027 mmol) in MeOH (0.5 mL) was treated with HCl (4.0M solutionin dioxane, 2.0 mL) at room temperature for 2 h. Solvents were removedand the residue was treated with aqueous NaHCO₃, and extracted withethyl acetate. The organic layer was dried, evaporated to afford thedesired intermediate as a yellowish solid (6.5 mg, yield 53%).

N-(2,6-dichloro-3-fluorobenzyl)-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine:A solution ofN-[(E)-(2,6-dichloro-3-fluorophenyl)methylidene]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine(35 mg, 0.063 mmol) in MeOH (5 mL) was treated with excess amount ofNaBH₄ under reflux. HPLC check indicated disappearance of the startingmaterial. The mixture was diluted with aqueous NaHCO₃, and extractedwith ethyl acetate. The organic solution was dried and evaporated.

Removal of the BOC protecting group was achieved using HCl/dioxane asdescribed in Example 18 to afford the product as a white solid (27 mg.94% yield).

Example 28N-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-6-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[3,2-b]pyridin-1-amine

The entitled compound was prepared as described in example 27 bycondensing tert-butyl4-[4-(1-amino-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(prepared in example 18:100 mg, 0.26 mmol) with1-(2,6-dichloro-3-fluorophenyl)ethanone (excess). The reduction of imineand BOC-deprotection were also carried out as described in Example 27.

Example 29 Biological Evaluation of Compounds

Compounds of this invention are evaluated in a variety of assays todetermine their biological activities. For example, the compounds of theinvention are tested for their ability to inhibit various proteinkinases of interest. Some of the compounds tested displayed potentnanomolar activity against the kinase Alk. Furthermore some of thesecompounds were screened for antiproliferative activity in the humanKarpas-299 and in the human SU-DHL-1 lymphoma cell lines. The compoundscan also be evaluated for their cytotoxic or growth inhibitory effectson tumor cells of interest, e.g., as described in more detail below andas shown above for some representative compounds. See e.g., WO03/000188, pages 115-136, the full contents of which are incorporatedherein by reference.

Some representative compounds of this invention are depicted below:

Kinase Inhibition

More specifically, the compounds described herein are screened forkinase inhibition activity as follows. Kinases suitable for use in thefollowing protocol include, but are not limited to: ALK, Jak2, b-Raf,c-Met, Tie-2, FLT3, Abl, Lck, Lyn, Src, Fyn, Syk, Zap-70, Itk, Tec, Btk,EGFR, ErbB2, Kdr, FLT1, Tek, InsR, and AKT.

Kinases are expressed as either kinase domains or full length constructsfused to glutathione S-transferase (GST) or polyHistidine tagged fusionproteins in either E. coli or Baculovirus-High Five expression systems.They are purified to near homogeneity by affinity chromatography aspreviously described (Lehr et al., 1996; Gish et al., 1995). In someinstances, kinases are co-expressed or mixed with purified or partiallypurified regulatory polypeptides prior to measurement of activity.

Kinase activity and inhibition can be measured by established protocols(see e.g., Braunwalder et al., 1996). In such cases, the transfer of³³P0₄ from ATP to the synthetic substrates poly(Glu, Tyr) 4:1 orpoly(Arg, Ser) 3:1 attached to the bioactive surface of microtiterplates is taken as a measure of enzyme activity. After an incubationperiod, the amount of phosphate transferred is measured by first washingthe plate with 0.5% phosphoric acid, adding liquid scintillant, and thencounting in a liquid scintillation detector. The IC₅₀ is determined bythe concentration of compound that causes a 50% reduction in the amountof ³³P incorporated onto the substrate bound to the plate.

Other methods relying upon the transfer of phosphate to peptide orpolypeptide substrate containing tyrosine, serine, threonine orhistidine, alone, in combination with each other, or in combination withother amino acids, in solution or immobilized (i.e., solid phase) arealso useful.

For example, transfer of phosphate to a peptide or polypeptide can alsobe detected using scintillation proximity, Fluorescence Polarization andhomogeneous time-resolved fluorescence. Alternatively, kinase activitycan be measured using antibody-based methods in which an antibody orpolypeptide is used as a reagent to detect phosphorylated targetpolypeptide.

For additional background information on such assay methodologies, seee, g., Braunwalder et al., 1996, Anal. Biochem. 234(1):23; Cleaveland etal., 1990, Anal Biochem. 190(2):249 Gish et al. (1995). Protein Eng.8(6):609 Kolb et al. (1998). Drug Discov. Toda V. 3:333 Lehr et al.(1996). Gene 169(2):27527-87 Seethala et al. (1998). Anal Biochem.255(2):257 Wu et al. (2000).

The inhibition of ALK tyrosine kinase activity can be demonstrated usingknown methods. For example, in one method, compounds can be tested fortheir ability to inhibit kinase activity of baculovirus-expressed ALKusing a modification of the ELISA protocol reported for trkA in Angeles,T. S. et al., Anal. Biochem. 1996, 236, 49-55, which is incorporatedherein by reference. Phosphorylation of the substrate, phopholipaseC-gamma (PLC-γ) generated as a fusion protein withglutathione-S-transferase (GST) as reported in rotin, D. et al., EMBO J.1992, 11, 559-567, which is incorporated by reference, can be detectedwith europium-labeled anti-phosphotyrosine antibody and measured bytime-resolved fluorescence (TRF). In this assay, 96-well plate is coatedwith 100 μL/well of 10 μg/mL substrate (phospholipase C-γ intris-buffered saline (TBS). The assay mixture (total volume=100 μL/well)consisting of 20 nM HEPES (pH 7.2, 1 μMATP (K_(m) level), 5 nM MnCl₂,0.1% BSA, 2.5% DMSO, and various concentrations of test compound is thenadded to the assay plate. The reaction is initiated by adding the enzyme(30 ng/mL ALK) and is allowed to proceed at 37 degrees C. for 15minutes. Detection of the phosphorylated product can be performed byadding 100 μL/well of Eu—N1 labeled PT66 antibody (Perkim Elmer #AD0041). Incubation at 37 degrees C. then proceeds for one hour,followed by addition of 100 □L enhancement solution (for example Wallac# 1244-105). The plate is gently agitated and after thirty minutes, thefluorescence of the resulting solution can be measured (for exampleusing EnVision 2100 (or 2102) multilabel plate reader from PerkinElmer).

Data analysis can then be performed. IC₅₀ values can be calculated byplotting percent inhibition versus log₁₀ of concentration of compound.

The inhibition of ALK tyrosine kinase activity can also be measuredusing the recombinant kinase domain of the ALK in analogy to VEDG-Rkinase assay described in J. Wood et al., Cancer Res 2000, 60,2178-2189. In vitro enzyme assays using GST-ALK protein tyrosine kinasecan be performed in 96-well plate as a filter binding assay in 20mMTris.HCl, pH 7.5, 3 mM MgCl₂, 10 mM MnCl₂, 1 nM DTT, 0.1 μCi/assay(=30 μL) [γ-³³P]-ATP, 2 μM ATP, 3 μg/mL poly (Glu, tyr 4:1) Poly-EY(sigma P-0275), 1% DMSO, 25 ng ALK enzyme. Assays can be incubated for10 mM, at ambient temperature. Reactions can be terminated by adding 50μL of 125 mM EDTA, and the reaction mixture can be transferred onto aMAIP Multiscreen plate (Millipore, Bedford, Mass.) previously wet withmethanol, and rehydrated for 5 minutes with water. Following washing(0.5% H₃PO₄), plates can be counted in a liquid scintillation counter.IC₅₀ values are calculated by linear regression analysis of thepercentage inhibition.

IC₅₀ values in the low nanomolar range have been observed for compoundsof this invention against various kinases, including ALK and Met.

Cell-Based Assays

Certain compounds of this invention have also been demonstratedcytotoxic or growth inhibitory effects on tumor and other cancer celllines and thus may be useful in the treatment of cancer and other cellproliferative diseases. Compounds are assayed for anti-tumor activityusing in vivo and in vitro assays which are well known to those skilledin the art. Generally, initial screens of compounds to identifycandidate anti-cancer drugs are performed in cellular assays. Compoundsidentified as having anti-proliferative activity in such cell-basedassays can then be subsequently assayed in whole organisms foranti-tumor activity and toxicity. Generally speaking, cell-based screenscan be performed more rapidly and cost-effectively relative to assaysthat use whole organisms. For purposes of this invention, the terms“anti-tumor” and “anti-cancer” activity are used interchangeably.

Cell-based methods for measuring antiproliferative activity are wellknown and can be used for comparative characterization of compounds ofthis invention. In general, cell proliferation and cell viability assaysare designed to provide a detectable signal when cells are metabolicallyactive. Compounds may be tested for antiproliferative activity bymeasuring any observed decrease in metabolic activity of the cells afterexposure of the cells to compound. Commonly used methods include, forexample, measurement of membrane integrity (as a measure of cellviability)(e.g. using trypan blue exclusion) or measurement of DNAsynthesis (e.g. by measuring incorporation of BrdU or 3H-thymidine).

Some methods for assaying cell proliferation use a reagent that isconverted into a detectable compound during cell proliferation.Particularly preferred compounds are tetrazolium salts and includewithout limitation MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide;Sigma-Aldrich, St. Louis, Mo.), MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium),XTT(2,3-bis(2-Methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide),INT, NBT, and NTV (Bernas et al. Biochim Biophys Acta 1451(1):73-81,1999). More commonly used assays utilizing tetrazolium salts detect cellproliferation by detecting the product of the enzymatic conversion ofthe tetrazolium salts into blue formazan derivatives, which are readilydetected by spectroscopic methods (Mosman. J. Immunol. Methods.65:55-63, 1983).

Other methods for assaying cell proliferation involve incubating cellsin a desired growth medium with and without the compounds to be tested.Growth conditions for various prokaryotic and eukaryotic cells arewell-known to those of ordinary skill in the art (Ausubel et al. CurrentProtocols in Molecular Biology. Wiley and Sons. 1999; Bonifacino et al.Current Protocols in Cell Biology. Wiley and Sons. 1999 bothincorporated herein by reference). To detect cell proliferation, thetetrazolium salts are added to the incubated cultured cells to allowenzymatic conversion to the detectable product by active cells. Cellsare processed, and the optical density of the cells is determined tomeasure the amount of formazan derivatives. Furthermore, commerciallyavailable kits, including reagents and protocols, are available forexamples, from Promega Corporation (Madison, Wis.), Sigma-Aldrich (St.Louis, Mo.), and Trevigen (Gaithersburg, Md.).

In addition, a wide variety of cell types may be used to screencompounds for antiproliferative activity, including the following celllines, among others: COLO 205 (colon cancer), DLD-1 (colon cancer),HCT-15 (colon cancer), HT29 (colon cancer), HEP G2 (Hepatoma), K-562(Leukemia), A549 (Lung), NCI-H249 (Lung), MCF7 (Mammary), MDA-MB-231(Mammary), SAOS-2 (Osteosarcoma), OVCAR-3 (Ovarian), PANC-1 (Pancreas),DU-145 (Prostate), PC-3 (Prostate), ACHN (Renal), CAKI-1 (Renal), MG-63(Sarcoma).

While the cell line is preferably mammalian, lower order eukaryoticcells such as yeast may also be used to screen compounds. Preferredmammalian cell lines are derived from humans, rats, mice, rabbits,monkeys, hamsters, and guinea pigs since cells lines from theseorganisms are well-studied and characterized. However, others may beused as well.

Suitable mammalian cell lines are often derived from tumors. Forexample, the following tumor cell-types may be sources of cells forculturing cells: melanoma, myeloid leukemia, carcinomas of the lung,breast, ovaries, colon, kidney, prostate, pancreas and testes),cardiomyocytes, endothelial cells, epithelial cells, lymphocytes (T-celland B cell), mast cells, eosinophils, vascular intimal cells,hepatocytes, leukocytes including mononuclear leukocytes, stem cellssuch as haemopoetic, neural, skin, lung, kidney, liver and myocyte stemcells (for use in screening for differentiation and de-differentiationfactors), osteoclasts, chondrocytes and other connective tissue cells,keratinocytes, melanocytes, liver cells, kidney cells, and adipocytes.Non-limiting examples of mammalian cells lines that have been widelyused by researchers include HeLa, NIH/3T3, HT1080, CHO, COS-1, 293T,WI-38 and CV1/EBNA-1.

Other cellular assays may be used which rely upon a reporter gene todetect metabolically active cells. Non-limiting examples of reportergene expression systems include green fluorescent protein (GFP), andluciferase. As an example of the use of GFP to screen for potentialantitumor drugs, Sandman et al. (Chem. Biol. 6:541-51; incorporatedherein by reference) used HeLa cells containing an inducible variant ofGFP to detect compounds that inhibited expression of the GFP, and thusinhibited cell proliferation.

An example of cell-based assay is shown as below. The cell lines thatcan be used in the assay are Ba/F3, a murine pro-B cell line, which hasbeen stably transfected with an expression vector PClneo™ (PromegaCorp., Madison Wis.) coding for NPM-ALK and subsequent selection of G418resistant cells. Non-transfected Ba/F3 cells depend on IL-3 for cellsurvival. In contrast NPM-ALK expressing Ba/F3 cells (namedBa/F3-NPM-ALK) can proliferate in the absence of IL-3 because theyobtain proliferative signal through NMP-ALK kinase. Putative inhibitorsof NPM-ALK kinase therefore abolish the growth signal and result inantiproliferative activity. The antiproliferative activity of inhibitorsof the NPM-ALK kinase can however be overcome by addition of IL-3 whichprovides growth signals through an NPM-ALK independent mechanism. For ananalogous cell system using FLT3 kinase see E. Weisberg et al. Cancercell, 2002, 1, 433-443. The inhibitory activity of the compounds offormula I can be determined as follows: BaF3-NPM-ALK cells(15,000/microtitre plate well) can be transferred to a 96-wellmicrotitre plates. The test compound (dissolved in DMSO) is then addedin a series of concentrations (dilution series) in such a manner thatthe final concentration of DMSO is not greater than 1% (v/v). After theaddition, the plates can be incubated for two days during which thecontrol cultures without test compound are able to undergo twocell-division cycles. The growth of BaF3-NPM-ALK cells can be measuredby means of Yopro™ staining (T Idziorek et al., J. Immunol. Methods1995, 185, 249-258). 25 μL of lysis buffer consisting of 20 mM sodiumcitrate, pH 4.0, 26.8 nM sodium chloride, 0.4% NP40, 20 mM EDTA and 20mM is added into each well. Cell lysis is completed within 60 minutes atroom temperature and total amount of Yopro bound to DNA is determined bymeasurement using for example a CytoFluor II 96-well reader (PerSeptiveBiosystems). The IC₅₀ can be determined by a computer aided system usingthe formula:

IC₅₀=[(ABS_(test)−ABS_(start))/(ABS_(control)−ABS_(start))]×100 in whichABS is absorption. The IC₅₀ value in such an experiment is given as thatconcentration of the test compound in question that results in a cellcount that is 50% lower than that obtained using the control withoutinhibitor.

The antiproliferative action of the compounds of this invention can alsobe determined in the human KARPAS-299 lymphoma cell line by means of animmunoblot as described in WG Dirks et al. Int. J. Cancer 2002, 100,49-56., using the methodology described above for the BaF3-NPM-ALK cellline.

In another example, antiproliferative activity can be determined usingKARPAS-299 lumphoma cell line in the following procedure: Compounds ofthe invention were incubated with the cells for 3 days, and the numberof viable cells in each well was measured indirectly using an MTStetrazolium assay (Promega). This assay is a colorimetric method fordetermining the number of viable cells through measurement of theirmetabolic activity. For example the detection of the product of theenzymatic conversion of tetrazolium salts into blue formazan derivativesis achieved by measuring absorbance at 490 nm using a plate reader. 40μL of the MTS reagent was added to all wells except the edge wells andthen the plates were returned to the incubator at 37° C. for 2 hours.The absorbance in each well was then measured at 490 nm using a WallacVictor²V plate reader. The IC₅₀ was calculated by determining theconcentration of compound required to decrease the MTS signal by 50% inbest-fit curves using Microsoft XLfit software, by comparing withbaseline, the DMSO control, as 0% inhibition.

Several compounds of Formula I exhibit inhibitory activity with an IC₅₀in the range of 10 nM to 200 nM.

Compounds identified by such cellular assays as having anti-cellproliferation activity are then tested for anti-tumor activity in wholeorganisms. Preferably, the organisms are mammalian. Well-characterizedmammalians systems for studying cancer include rodents such as rats andmice. Typically, a tumor of interest is transplanted into a mouse havinga reduced ability to mount an immune response to the tumor to reduce thelikelihood of rejection. Such mice include for example, nude mice(athymic) and SCID (severe combined immunodeficiency) mice. Othertransgenic mice such as oncogene containing mice may be used in thepresent assays (see for example U.S. Pat. No. 4,736,866 and U.S. Pat.No. 5,175,383). For a review and discussion on the use of rodent modelsfor antitumor drug testing see Kerbel (Cancer Metastasis Rev.17:301-304, 1998-99).

In general, the tumors of interest are implanted in a test organismpreferably subcutaneously. The organism containing the tumor is treatedwith doses of candidate anti-tumor compounds. The size of the tumor isperiodically measured to determine the effects of the test compound onthe tumor. Some tumor types are implanted at sites other thansubcutaneous sites (e.g. intraperitoneal sites) and survival is measuredas the endpoint. Parameters to be assayed with routine screening includedifferent tumor models, various tumor and drug routes, and dose amountsand schedule. For a review of the use of mice in detecting antitumorcompounds see Corbett et al. (Invest New Drugs. 15:207-218, 1997;incorporated herein by reference).

Example 30 Pharmaceutical Compositions

Representative pharmaceutical dosage forms of the compounds of thisinvention (the active ingredient being referred to as “Compound”), areprovided for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound 100 Lactose Ph.Eur 182.75 Croscarmellosesodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate3.0

(b) Tablet II mg/tablet Compound 50 Lactose Ph.Eur 223.75 Croscarmellosesodium 6.0 Maize starch 15.0 Polyvinylpyffolidone (5% w/v paste) 2.25Magnesium stearate 3.0

(c) Tablet III mg/tablet Compound 1.0 Lactose Ph.Eur 93.25Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75Magnesium stearate 1.0-76

(d) Capsule mg/capsule Compound 10 Lactose Ph.Eur 488.5 Magnesium 1.5

(e) Injection I (50 mg/ml) Compound  5.0% w/v 1M Sodium hydroxidesolution 15.0% v/v 0. IM Hydrochloric acid (to adjust pH to 7.6)  4.5%w/v Polyethylene glycol 400

Water for injection to 100%

(f) Injection II (10 mg/ml) Compound  1.0% W/v Sodium phosphate BP  3.6%w/v O. 1M Sodium hydroxide solution 15.0% v/v

Water for injection to 100%

(g) Injection III (1 mg/ml, buffered to pH6) Compound  0.1% w/v Sodiumphosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v

Water for injection to 100%

(h) Aerosol 1 mg/ml Compound 10.0 Sorbitan trioleate 13.5Trichlorofluoromethane 910.0 Dichlorodifluoromethane 490.0

(i) Aerosol II mg/ml Compound 0.2 Sorbitan trioleate 0.27Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0Dichlorotetrafluoroethane 1094.0

(j) Aerosol III mg/ml Compound 2.5 Sorbitan trioleate 3.38Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6

(k) Aerosol IV mg/ml Compound 2.5 Soya lecithin 2.7Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0Dichlorotetrafluoroethane 191.6

(1) Ointment ml Compound  40 mg Ethanol 300 μl Water 300 μl1-Dodecylazacycloheptan one  50 μl Propylene glycol   1 ml Note: Theseformulations may be prepared using conventional procedures well known inthe pharmaceutical art. The tablets (a)-(c) may be enteric coated byconventional means, if desired to provide a coating of cellulose acetatephthalate, for example. The aerosol formulations (h)-(k) may be used inconjunction with standard, metered dose aerosol dispensers, and thesuspending agents sorbitan trioleate and soya lecithin may be replacedby an alternative suspending agent such as sorbitan monooleate, sorbitansesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

1. A compound, tautomer or pharmaceutically acceptable salt of Formula1, or a tautomer or pharmaceutically acceptable salt

thereof: wherein Ring A is a 6-membered heteroaryl ring, which: (a)comprises carbon atoms and 1 to 3 nitrogen atoms; (b) bears asubstituent, Ring C, on the first or second ring atom adjacent to theRing A nitrogen depicted in Formula 1; and, (c) bears 0-2 R^(a) groups;Ring B is a 5-membered heteroaryl ring comprising carbon atoms and 1 to3 nitrogen atoms; L¹ is C(O), CR⁴R⁵ or a bond; X is O or NR⁴; Ring C isan aryl, a 3- to 8-membered carbocyclyl or a 5-, 6- or 7-memberedheterocyclic or heteroaryl ring comprising carbon atoms and 1-4heteroatoms independently selected from O, N, P(O) and S(O)_(r); Ring Cis optionally substituted on carbon or on the heteroatom(s) with 1-5R^(c) groups; Ring D is an aryl or a 5- or 6-membered heteroaryl ringcomprising carbon atoms and 1 to 4 heteroatoms independently selectedfrom O, N and S, and Ring D is optionally substituted with 1 to 5 R^(d)groups; R^(a) and R^(d) are independently selected from the groupconsisting of halo, —CN, —NO₂, —OR², —O—NR¹R², —NR¹R², —NR¹—NR¹R²,—NR¹—OR², —C(O)YR², —OC(O)YR², —NR¹C(O)YR², —SC(O)YR², —NR¹C(═S)YR²,—OC(═S)YR², —C(═S)YR², —YC(═NR¹)YR², —YC(═N—OR¹)YR², —YC(═N—NR¹R²)YR²,—YP(═O)(YR³)(YR³), —Si(R³)₃, —NR¹SO₂R², —S(O)_(r)R², —SO₂NR¹R² and—NR¹SO₂NR¹R²; R^(c) is R^(a) or ═O or ═S; or alternatively two adjacentR^(a) moieties, two adjacent R^(c) moieties or two adjacent R^(d)moieties can form with the atoms to which they are attached a 5-, 6- or7-membered saturated, partially saturated or unsaturated ring,optionally substituted; and which contains 0-4 heteroatoms selected fromN, O, P(O) and S(O)_(r); r is 0, 1 or 2; n is 0, 1 or 2; p is 0, 1, 2,3, 4 or 5; s is 0, 1, 2, 3, 4 or 5; each occurrence of Y isindependently a bond, —O—, —S— or —NR¹—; each occurrence of R¹ and R² isindependently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; eachoccurrence of R³ is independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic andheteroaryl; R⁴ and R⁵ are independently selected from H or a C₁₋₆alkyl;alternatively, each NR¹R² moiety may be a 5-, 6- or 7-memberedsaturated, partially saturated or unsaturated ring, which can beoptionally substituted and which contains 0-3 additional heteroatomsselected from N, O, P(O) and S(O)_(r); and each of the foregoing alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl and heterocyclic moiety is optionally substituted. 2-3.(canceled)
 4. The compound of claim 1, or a tautomer or pharmaceuticallyacceptable salt thereof, in which Ring A is selected from the following:


5. The compound of claim 1, or a tautomer or pharmaceutically acceptablesalt thereof, in which Ring B is selected from the following:

6-13. (canceled)
 14. The compound of any of claims 1, 4, 5, or atautomer or pharmaceutically acceptable salt thereof, in which X is O.15. The compound of any of claims 1, 4, 5, or a tautomer orpharmaceutically acceptable salt thereof, in which X is NR⁴.
 16. Thecompound of any of claims 1, 4, 5, or a tautomer or pharmaceuticallyacceptable salt thereof, in which Ring D is an optionally substitutedaryl group.
 17. The compound of any of claims 1, 4, 5, or a tautomer orpharmaceutically acceptable salt thereof, in which Ring D is anoptionally substituted 5- or 6-membered heteroaryl group.
 18. Thecompound of any of claims 1, 4, 5, or a tautomer or pharmaceuticallyacceptable salt thereof, in which Ring C is an optionally substitutedaryl.
 19. The compound of any of claims 1, 4, 5, or a tautomer orpharmaceutically acceptable salt thereof, in which Ring C is anoptionally substituted 5-membered ring heteroaryl.
 20. The compound ofclaim 19, or a tautomer or pharmaceutically acceptable salt thereof, inwhich Ring C is an optionally substituted pyrazole. 21-28. (canceled)29. The compound of claim 1, or a tautomer or pharmaceuticallyacceptable salt thereof, of Formula VI or Formula VI:


30. The compound, tautomer or pharmaceutically acceptable salt of claim29 in which X is NR⁴.
 31. The compound, tautomer or pharmaceuticallyacceptable salt of claim 30 in which L¹ is C(O).
 32. The compound,tautomer or pharmaceutically acceptable salt of claim 29 in which X isO.
 33. The compound, tautomer or pharmaceutically acceptable salt ofclaim 30 in which L¹ is CR⁴R⁵.
 34. The compound, tautomer orpharmaceutically acceptable salt of claim 33 in which L¹ is CH₂ orCH(CH₃).
 35. The compound, tautomer or pharmaceutically acceptable saltof claim 29 in which Ring D is an optionally substituted 5- or6-membered heteroaryl ring.
 36. The compound, tautomer orpharmaceutically acceptable salt of claim 29 in which Ring D is anoptionally substituted aryl Ling.
 37. The compound, tautomer orpharmaceutically acceptable salt of claim 29 in which R^(c) is anoptionally substituted alkyl or an optionally substituted heterocycylring.
 38. The compound, tautomer or pharmaceutically acceptable salt ofclaim 37 in which R^(c) is selected from piperidine or pyrrolidine. 39.Compounds of claim 1 of a formula selected from the following:


40. (canceled)
 41. The compound, tautomer or pharmaceutically acceptablesalt of claim 39 in which Ring C is an optionally substituted phenyl oran optionally substituted pyrazole and Ring D is an optionallysubstituted phenyl.
 42. The compound, tautomer or pharmaceuticallyacceptable salt of claims 1, 4, 5, 29, 39 or 41 in which p is 1, 2 or 3;each R^(d) is independently selected from halo or CF₃, n is 0, s is 0 or1 and R^(c) is lower alkyl, halo, heterocyclyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, heterocyclylalkyl, SO₂NH₂, SO₂NH(alkyl),SO₂N(alkyl)₂, O-alkyl, S-alkyl, C(═O)alkyl, NH₂, NH-alkyl, N(Alkyl)₂,C(O)NH₂, C(═O)NH(alkyl) or C(═O)N(alkyl)₂.
 43. A method for treatingcancer in a mammal in need thereof, comprising administering to themammal a therapeutically effective amount of a compound, tautomer orpharmaceutically acceptable salt of any of the claims 1, 4, 5, 29, 39,41, 42 or 46-51; or a pharmaceutically acceptable salt, solvate orhydrate thereof.
 44. A method of claim 43 in which the cancer isnon-small-cell lung cancer, gliosblastoma, neuroblastoma, esophagealcarcinomas, diffuse large B-cell lymphomas, breast cancer,rhabdomyosarcomas, anaplastic large-cell lymphomas and inflammatorymyofibroblastic tumors.
 45. A composition comprising a compound,tautomer or pharmaceutically acceptable salt of any of the claims 1, 4,5, 29, 39, 41, 42 or 46-51 and a pharmaceutical carrier, diluent orvehicle.
 46. The compound, tautomer or pharmaceutically acceptable saltof claim 35 in which X is NR⁴.
 47. The compound, tautomer orpharmaceutically acceptable salt of claim 46 in which L¹ is C(O). 48.The compound, tautomer or pharmaceutically acceptable salt of claim 35in which X is O.
 49. The compound, tautomer or pharmaceuticallyacceptable salt of claim 35 in which in which L¹ is CR⁴R⁵.
 50. Thecompound, tautomer or pharmaceutically acceptable salt of claim 49 inwhich L¹ is CH₂ or CH(CH₃).
 51. The compound, tautomer orpharmaceutically acceptable salt of claim 32 in which L¹ is CR⁴R⁵.